Daily Papers

Histopathology and transcriptomics are fundamental modalities in oncology, encapsulating the morphological and molecular aspects of the disease. Multi-modal self-supervised learning has demonstrated remarkable potential in learning pathological representations by integrating diverse data sources. Conventional multi-modal integration methods primarily emphasize modality alignment, while paying insufficient attention to retaining the modality-specific structures. However, unlike conventional scenarios where multi-modal inputs share highly overlapping features, histopathology and transcriptomics exhibit pronounced heterogeneity, offering orthogonal yet complementary insights. Histopathology provides morphological and spatial context, elucidating tissue architecture and cellular topology, whereas transcriptomics delineates molecular signatures through gene expression patterns. This inherent disparity introduces a major challenge in aligning them while maintaining modality-specific fidelity. To address these challenges, we present MIRROR, a novel multi-modal representation learning method designed to foster both modality alignment and retention. MIRROR employs dedicated encoders to extract comprehensive features for each modality, which is further complemented by a modality alignment module to achieve seamless integration between phenotype patterns and molecular profiles. Furthermore, a modality retention module safeguards unique attributes from each modality, while a style clustering module mitigates redundancy and enhances disease-relevant information by modeling and aligning consistent pathological signatures within a clustering space. Extensive evaluations on TCGA cohorts for cancer subtyping and survival analysis highlight MIRROR's superior performance, demonstrating its effectiveness in constructing comprehensive oncological feature representations and benefiting the cancer diagnosis.

We present a novel approach for the prediction of anticancer compound sensitivity by means of multi-modal attention-based neural networks (PaccMann). In our approach, we integrate three key pillars of drug sensitivity, namely, the molecular structure of compounds, transcriptomic profiles of cancer cells as well as prior knowledge about interactions among proteins within cells. Our models ingest a drug-cell pair consisting of SMILES encoding of a compound and the gene expression profile of a cancer cell and predicts an IC50 sensitivity value. Gene expression profiles are encoded using an attention-based encoding mechanism that assigns high weights to the most informative genes. We present and study three encoders for SMILES string of compounds: 1) bidirectional recurrent 2) convolutional 3) attention-based encoders. We compare our devised models against a baseline model that ingests engineered fingerprints to represent the molecular structure. We demonstrate that using our attention-based encoders, we can surpass the baseline model. The use of attention-based encoders enhance interpretability and enable us to identify genes, bonds and atoms that were used by the network to make a prediction.

Molecular "fingerprints" encoding structural information are the workhorse of cheminformatics and machine learning in drug discovery applications. However, fingerprint representations necessarily emphasize particular aspects of the molecular structure while ignoring others, rather than allowing the model to make data-driven decisions. We describe molecular "graph convolutions", a machine learning architecture for learning from undirected graphs, specifically small molecules. Graph convolutions use a simple encoding of the molecular graph---atoms, bonds, distances, etc.---which allows the model to take greater advantage of information in the graph structure. Although graph convolutions do not outperform all fingerprint-based methods, they (along with other graph-based methods) represent a new paradigm in ligand-based virtual screening with exciting opportunities for future improvement.

In drug-discovery-related tasks such as virtual screening, machine learning is emerging as a promising way to predict molecular properties. Conventionally, molecular fingerprints (numerical representations of molecules) are calculated through rule-based algorithms that map molecules to a sparse discrete space. However, these algorithms perform poorly for shallow prediction models or small datasets. To address this issue, we present SMILES Transformer. Inspired by Transformer and pre-trained language models from natural language processing, SMILES Transformer learns molecular fingerprints through unsupervised pre-training of the sequence-to-sequence language model using a huge corpus of SMILES, a text representation system for molecules. We performed benchmarks on 10 datasets against existing fingerprints and graph-based methods and demonstrated the superiority of the proposed algorithms in small-data settings where pre-training facilitated good generalization. Moreover, we define a novel metric to concurrently measure model accuracy and data efficiency.

Foundation models applied to bio-molecular space hold promise to accelerate drug discovery. Molecular representation is key to building such models. Previous works have typically focused on a single representation or view of the molecules. Here, we develop a multi-view foundation model approach, that integrates molecular views of graph, image and text. Single-view foundation models are each pre-trained on a dataset of up to 200M molecules and then aggregated into combined representations. Our multi-view model is validated on a diverse set of 18 tasks, encompassing ligand-protein binding, molecular solubility, metabolism and toxicity. We show that the multi-view models perform robustly and are able to balance the strengths and weaknesses of specific views. We then apply this model to screen compounds against a large (>100 targets) set of G Protein-Coupled receptors (GPCRs). From this library of targets, we identify 33 that are related to Alzheimer's disease. On this subset, we employ our model to identify strong binders, which are validated through structure-based modeling and identification of key binding motifs.

In line with recent advances in neural drug design and sensitivity prediction, we propose a novel architecture for interpretable prediction of anticancer compound sensitivity using a multimodal attention-based convolutional encoder. Our model is based on the three key pillars of drug sensitivity: compounds' structure in the form of a SMILES sequence, gene expression profiles of tumors and prior knowledge on intracellular interactions from protein-protein interaction networks. We demonstrate that our multiscale convolutional attention-based (MCA) encoder significantly outperforms a baseline model trained on Morgan fingerprints, a selection of encoders based on SMILES as well as previously reported state of the art for multimodal drug sensitivity prediction (R2 = 0.86 and RMSE = 0.89). Moreover, the explainability of our approach is demonstrated by a thorough analysis of the attention weights. We show that the attended genes significantly enrich apoptotic processes and that the drug attention is strongly correlated with a standard chemical structure similarity index. Finally, we report a case study of two receptor tyrosine kinase (RTK) inhibitors acting on a leukemia cell line, showcasing the ability of the model to focus on informative genes and submolecular regions of the two compounds. The demonstrated generalizability and the interpretability of our model testify its potential for in-silico prediction of anticancer compound efficacy on unseen cancer cells, positioning it as a valid solution for the development of personalized therapies as well as for the evaluation of candidate compounds in de novo drug design.

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial datasets spanning a wide variety of chemical endpoints. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary datasets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.

Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm.

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging the relevant information from the omics data modalities provides the statistical basis for determining suitable therapies for specific cancer patients. Different data modalities may each have their specific structures that need to be taken into account during inference. In this paper, we assume that each omics data modality has a low-rank structure with only few relevant features that affect the prediction and we propose to use a composite local nuclear norm penalization for learning drug sensitivity. Numerical results show that the composite low-rank structure can improve the prediction performance compared to using a global low-rank approach or elastic net regression.

Molecular representation is a foundational element in our understanding of the physical world. Its importance ranges from the fundamentals of chemical reactions to the design of new therapies and materials. Previous molecular machine learning models have employed strings, fingerprints, global features, and simple molecular graphs that are inherently information-sparse representations. However, as the complexity of prediction tasks increases, the molecular representation needs to encode higher fidelity information. This work introduces a novel approach to infusing quantum-chemical-rich information into molecular graphs via stereoelectronic effects. We show that the explicit addition of stereoelectronic interactions significantly improves the performance of molecular machine learning models. Furthermore, stereoelectronics-infused representations can be learned and deployed with a tailored double graph neural network workflow, enabling its application to any downstream molecular machine learning task. Finally, we show that the learned representations allow for facile stereoelectronic evaluation of previously intractable systems, such as entire proteins, opening new avenues of molecular design.

Early identification of sensitive cancer cell lines is essential for accelerating biomarker discovery and elucidating drug mechanism of action. Given the efficiency and low cost of small-scale drug screens relative to extensive omics profiling, we compared drug-response panel (DRP) descriptors against omics features for predictive capacity using gradient boosting tree models across the GDSC and CCLE drug response datasets. DRP descriptors consistently outperformed omics data across key performance metrics, with variable performance across different drugs. Using complementary explainability approaches, we confirmed known MAPK-inhibitor sensitivity signatures, and identified novel potential biomarker candidates for MEK1/2 and BTK/MNK inhibitors. Lastly, to demonstrate the utility of this approach in distinguishing phenotypes, we applied our models to the breast cancer line MCF7 versus the non-tumorigenic MCF10A, and successfully identified compounds that selectively inhibit MCF7 while sparing the non-tumorigenic MCF10A. This methodology, developed using focused drug and cell line panels, supports early-stage drug development by facilitating rational cell line selection and compound prioritisation, enabling more efficient biomarker identification and candidate assessment.

Machine learning, notably deep learning, has significantly propelled molecular investigations within the biochemical sphere. Traditionally, modeling for such research has centered around a handful of paradigms. For instance, the prediction paradigm is frequently deployed for tasks such as molecular property prediction. To enhance the generation and decipherability of purely data-driven models, scholars have integrated biochemical domain knowledge into these molecular study models. This integration has sparked a surge in paradigm transfer, which is solving one molecular learning task by reformulating it as another one. With the emergence of Large Language Models, these paradigms have demonstrated an escalating trend towards harmonized unification. In this work, we delineate a literature survey focused on knowledge-informed molecular learning from the perspective of paradigm transfer. We classify the paradigms, scrutinize their methodologies, and dissect the contribution of domain knowledge. Moreover, we encapsulate prevailing trends and identify intriguing avenues for future exploration in molecular learning.

With the advent of deep generative models in computational chemistry, in silico anticancer drug design has undergone an unprecedented transformation. While state-of-the-art deep learning approaches have shown potential in generating compounds with desired chemical properties, they disregard the genetic profile and properties of the target disease. Here, we introduce the first generative model capable of tailoring anticancer compounds for a specific biomolecular profile. Using a RL framework, the transcriptomic profiles of cancer cells are used as a context for the generation of candidate molecules. Our molecule generator combines two separately pretrained variational autoencoders (VAEs) - the first VAE encodes transcriptomic profiles into a smooth, latent space which in turn is used to condition a second VAE to generate novel molecular structures on the given transcriptomic profile. The generative process is optimized through PaccMann, a previously developed drug sensitivity prediction model to obtain effective anticancer compounds for the given context (i.e., transcriptomic profile). We demonstrate how the molecule generation can be biased towards compounds with high predicted inhibitory effect against individual cell lines or specific cancer sites. We verify our approach by investigating candidate drugs generated against specific cancer types and find the highest structural similarity to existing compounds with known efficacy against these cancer types. We envision our approach to transform in silico anticancer drug design by leveraging the biomolecular characteristics of the disease in order to increase success rates in lead compound discovery.

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Pretrained neural networks have attracted significant interest in chemistry and small molecule drug design. Embeddings from these models are widely used for molecular property prediction, virtual screening, and small data learning in molecular chemistry. This study presents the most extensive comparison of such models to date, evaluating 25 models across 25 datasets. Under a fair comparison framework, we assess models spanning various modalities, architectures, and pretraining strategies. Using a dedicated hierarchical Bayesian statistical testing model, we arrive at a surprising result: nearly all neural models show negligible or no improvement over the baseline ECFP molecular fingerprint. Only the CLAMP model, which is also based on molecular fingerprints, performs statistically significantly better than the alternatives. These findings raise concerns about the evaluation rigor in existing studies. We discuss potential causes, propose solutions, and offer practical recommendations.

Recently, pre-trained foundation models have enabled significant advancements in multiple fields. In molecular machine learning, however, where datasets are often hand-curated, and hence typically small, the lack of datasets with labeled features, and codebases to manage those datasets, has hindered the development of foundation models. In this work, we present seven novel datasets categorized by size into three distinct categories: ToyMix, LargeMix and UltraLarge. These datasets push the boundaries in both the scale and the diversity of supervised labels for molecular learning. They cover nearly 100 million molecules and over 3000 sparsely defined tasks, totaling more than 13 billion individual labels of both quantum and biological nature. In comparison, our datasets contain 300 times more data points than the widely used OGB-LSC PCQM4Mv2 dataset, and 13 times more than the quantum-only QM1B dataset. In addition, to support the development of foundational models based on our proposed datasets, we present the Graphium graph machine learning library which simplifies the process of building and training molecular machine learning models for multi-task and multi-level molecular datasets. Finally, we present a range of baseline results as a starting point of multi-task and multi-level training on these datasets. Empirically, we observe that performance on low-resource biological datasets show improvement by also training on large amounts of quantum data. This indicates that there may be potential in multi-task and multi-level training of a foundation model and fine-tuning it to resource-constrained downstream tasks.

Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations. However, current molecular representation learning methods do not provide a comprehensive view of cell states under these perturbations and struggle to remove noise, hindering model generalization. We introduce the Information Alignment (InfoAlign) approach to learn molecular representations through the information bottleneck method in cells. We integrate molecules and cellular response data as nodes into a context graph, connecting them with weighted edges based on chemical, biological, and computational criteria. For each molecule in a training batch, InfoAlign optimizes the encoder's latent representation with a minimality objective to discard redundant structural information. A sufficiency objective decodes the representation to align with different feature spaces from the molecule's neighborhood in the context graph. We demonstrate that the proposed sufficiency objective for alignment is tighter than existing encoder-based contrastive methods. Empirically, we validate representations from InfoAlign in two downstream tasks: molecular property prediction against up to 19 baseline methods across four datasets, plus zero-shot molecule-morphology matching.

Molecular Representation Learning (MRL) has proven impactful in numerous biochemical applications such as drug discovery and enzyme design. While Graph Neural Networks (GNNs) are effective at learning molecular representations from a 2D molecular graph or a single 3D structure, existing works often overlook the flexible nature of molecules, which continuously interconvert across conformations via chemical bond rotations and minor vibrational perturbations. To better account for molecular flexibility, some recent works formulate MRL as an ensemble learning problem, focusing on explicitly learning from a set of conformer structures. However, most of these studies have limited datasets, tasks, and models. In this work, we introduce the first MoleculAR Conformer Ensemble Learning (MARCEL) benchmark to thoroughly evaluate the potential of learning on conformer ensembles and suggest promising research directions. MARCEL includes four datasets covering diverse molecule- and reaction-level properties of chemically diverse molecules including organocatalysts and transition-metal catalysts, extending beyond the scope of common GNN benchmarks that are confined to drug-like molecules. In addition, we conduct a comprehensive empirical study, which benchmarks representative 1D, 2D, and 3D molecular representation learning models, along with two strategies that explicitly incorporate conformer ensembles into 3D MRL models. Our findings reveal that direct learning from an accessible conformer space can improve performance on a variety of tasks and models.

Molecular property prediction has gained significant attention due to its transformative potential in multiple scientific disciplines. Conventionally, a molecule graph can be represented either as a graph-structured data or a SMILES text. Recently, the rapid development of Large Language Models (LLMs) has revolutionized the field of NLP. Although it is natural to utilize LLMs to assist in understanding molecules represented by SMILES, the exploration of how LLMs will impact molecular property prediction is still in its early stage. In this work, we advance towards this objective through two perspectives: zero/few-shot molecular classification, and using the new explanations generated by LLMs as representations of molecules. To be specific, we first prompt LLMs to do in-context molecular classification and evaluate their performance. After that, we employ LLMs to generate semantically enriched explanations for the original SMILES and then leverage that to fine-tune a small-scale LM model for multiple downstream tasks. The experimental results highlight the superiority of text explanations as molecular representations across multiple benchmark datasets, and confirm the immense potential of LLMs in molecular property prediction tasks. Codes are available at https://github.com/ChnQ/LLM4Mol.

Large pretrained models such as GPT-3 have had tremendous impact on modern natural language processing by leveraging self-supervised learning to learn salient representations that can be used to readily finetune on a wide variety of downstream tasks. We investigate the possibility of transferring such advances to molecular machine learning by building a chemical foundation model, ChemBERTa-2, using the language of SMILES. While labeled data for molecular prediction tasks is typically scarce, libraries of SMILES strings are readily available. In this work, we build upon ChemBERTa by optimizing the pretraining process. We compare multi-task and self-supervised pretraining by varying hyperparameters and pretraining dataset size, up to 77M compounds from PubChem. To our knowledge, the 77M set constitutes one of the largest datasets used for molecular pretraining to date. We find that with these pretraining improvements, we are competitive with existing state-of-the-art architectures on the MoleculeNet benchmark suite. We analyze the degree to which improvements in pretraining translate to improvement on downstream tasks.

We introduce a convolutional neural network that operates directly on graphs. These networks allow end-to-end learning of prediction pipelines whose inputs are graphs of arbitrary size and shape. The architecture we present generalizes standard molecular feature extraction methods based on circular fingerprints. We show that these data-driven features are more interpretable, and have better predictive performance on a variety of tasks.

Large-scale molecular representation methods have revolutionized applications in material science, such as drug discovery, chemical modeling, and material design. With the rise of transformers, models now learn representations directly from molecular structures. In this study, we develop an encoder-decoder model based on BART that is capable of leaning molecular representations and generate new molecules. Trained on SELFIES, a robust molecular string representation, our model outperforms existing baselines in downstream tasks, demonstrating its potential in efficient and effective molecular data analysis and manipulation.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

Identifying drug-target interactions is essential for developing effective therapeutics. Binding affinity quantifies these interactions, and traditional approaches rely on computationally intensive 3D structural data. In contrast, language models can efficiently process sequential data, offering an alternative approach to molecular representation. In the current study, we introduce BAPULM, an innovative sequence-based framework that leverages the chemical latent representations of proteins via ProtT5-XL-U50 and ligands through MolFormer, eliminating reliance on complex 3D configurations. Our approach was validated extensively on benchmark datasets, achieving scoring power (R) values of 0.925 pm 0.043, 0.914 pm 0.004, and 0.8132 pm 0.001 on benchmark1k2101, Test2016_290, and CSAR-HiQ_36, respectively. These findings indicate the robustness and accuracy of BAPULM across diverse datasets and underscore the potential of sequence-based models in-silico drug discovery, offering a scalable alternative to 3D-centric methods for screening potential ligands.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

The success of drug discovery and development relies on the precise prediction of molecular activities and properties. While in silico molecular property prediction has shown remarkable potential, its use has been limited so far to assays for which large amounts of data are available. In this study, we use a fine-tuned large language model to integrate biological assays based on their textual information, coupled with Barlow Twins, a Siamese neural network using a novel self-supervised learning approach. This architecture uses both assay information and molecular fingerprints to extract the true molecular information. TwinBooster enables the prediction of properties of unseen bioassays and molecules by providing state-of-the-art zero-shot learning tasks. Remarkably, our artificial intelligence pipeline shows excellent performance on the FS-Mol benchmark. This breakthrough demonstrates the application of deep learning to critical property prediction tasks where data is typically scarce. By accelerating the early identification of active molecules in drug discovery and development, this method has the potential to help streamline the identification of novel therapeutics.

In this work, we present a method to generate a configurational level fingerprint for polymers using the Bead-Spring-Model. Unlike some of the previous fingerprinting approaches that employ monomer-level information where atomistic descriptors are computed using quantum chemistry calculations, this approach incorporates configurational information from a coarse-grained model of a long polymer chain. The proposed approach may be advantageous for the study of behavior resulting from large molecular weights. To create this fingerprint, we make use of two kinds of descriptors. First, we calculate certain geometric descriptors like Re2, Rg2 etc. and label them as Calculated Descriptors. Second, we generate a set of data-driven descriptors using an unsupervised autoencoder model and call them Learnt Descriptors. Using a combination of both of them, we are able to learn mappings from the structure to various properties of the polymer chain by training ML models. We test our fingerprint to predict the probability of occurrence of a configuration at equilibrium, which is approximated by a simple linear relationship between the instantaneous internal energy and equilibrium average internal energy.

The size, diversity, and quality of pretraining datasets critically determine the generalization ability of foundation models. Despite their growing importance in chemoinformatics, the effectiveness of molecular representation learning has been hindered by limitations in existing small molecule datasets. To address this gap, we present MolPILE, large-scale, diverse, and rigorously curated collection of 222 million compounds, constructed from 6 large-scale databases using an automated curation pipeline. We present a comprehensive analysis of current pretraining datasets, highlighting considerable shortcomings for training ML models, and demonstrate how retraining existing models on MolPILE yields improvements in generalization performance. This work provides a standardized resource for model training, addressing the pressing need for an ImageNet-like dataset in molecular chemistry.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Discovering novel drug candidate molecules is one of the most fundamental and critical steps in drug development. Generative deep learning models, which create synthetic data given a probability distribution, offer a high potential for designing de novo molecules. However, to be utilisable in real life drug development pipelines, these models should be able to design drug like and target centric molecules. In this study, we propose an end to end generative system, DrugGEN, for the de novo design of drug candidate molecules that interact with intended target proteins. The proposed method represents molecules as graphs and processes them via a generative adversarial network comprising graph transformer layers. The system is trained using a large dataset of drug like compounds and target specific bioactive molecules to design effective inhibitory molecules against the AKT1 protein, which is critically important in developing treatments for various types of cancer. We conducted molecular docking and dynamics to assess the target centric generation performance of the model, as well as attention score visualisation to examine model interpretability. In parallel, selected compounds were chemically synthesised and evaluated in the context of in vitro enzymatic assays, which identified two bioactive molecules that inhibited AKT1 at low micromolar concentrations. These results indicate that DrugGEN's de novo molecules have a high potential for interacting with the AKT1 protein at the level of its native ligands. Using the open access DrugGEN codebase, it is possible to easily train models for other druggable proteins, given a dataset of experimentally known bioactive molecules.

GNNs and chemical fingerprints are the predominant approaches to representing molecules for property prediction. However, in NLP, transformers have become the de-facto standard for representation learning thanks to their strong downstream task transfer. In parallel, the software ecosystem around transformers is maturing rapidly, with libraries like HuggingFace and BertViz enabling streamlined training and introspection. In this work, we make one of the first attempts to systematically evaluate transformers on molecular property prediction tasks via our ChemBERTa model. ChemBERTa scales well with pretraining dataset size, offering competitive downstream performance on MoleculeNet and useful attention-based visualization modalities. Our results suggest that transformers offer a promising avenue of future work for molecular representation learning and property prediction. To facilitate these efforts, we release a curated dataset of 77M SMILES from PubChem suitable for large-scale self-supervised pretraining.

The recent success of large foundation models in artificial intelligence has prompted the emergence of chemical pre-trained models. Despite the growing interest in large molecular pre-trained models that provide informative representations for downstream tasks, attempts for multimodal pre-training approaches on the molecule domain were limited. To address this, we present a novel multimodal molecular pre-trained model that incorporates the modalities of structure and biochemical properties, drawing inspiration from recent advances in multimodal learning techniques. Our proposed model pipeline of data handling and training objectives aligns the structure/property features in a common embedding space, which enables the model to regard bidirectional information between the molecules' structure and properties. These contributions emerge synergistic knowledge, allowing us to tackle both multimodal and unimodal downstream tasks through a single model. Through extensive experiments, we demonstrate that our model shows remarkable capabilities in solving various meaningful chemical challenges, including conditional molecule generation, property prediction, molecule classification, and reaction prediction.

Predicting gene function from its DNA sequence is a fundamental challenge in biology. Many deep learning models have been proposed to embed DNA sequences and predict their enzymatic function, leveraging information in public databases linking DNA sequences to an enzymatic function label. However, much of the scientific community's knowledge of biological function is not represented in these categorical labels, and is instead captured in unstructured text descriptions of mechanisms, reactions, and enzyme behavior. These descriptions are often captured alongside DNA sequences in biological databases, albeit in an unstructured manner. Deep learning of models predicting enzymatic function are likely to benefit from incorporating this multi-modal data encoding scientific knowledge of biological function. There is, however, no dataset designed for machine learning algorithms to leverage this multi-modal information. Here we propose a novel dataset and benchmark suite that enables the exploration and development of large multi-modal neural network models on gene DNA sequences and natural language descriptions of gene function. We present baseline performance on benchmarks for both unsupervised and supervised tasks that demonstrate the difficulty of this modeling objective, while demonstrating the potential benefit of incorporating multi-modal data types in function prediction compared to DNA sequences alone. Our dataset is at: https://hoarfrost-lab.github.io/BioTalk/.

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality labeled MS/MS spectra and defines three MS/MS annotation challenges: de novo molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at https://github.com/pluskal-lab/MassSpecGym.

Identifying a small molecule from its mass spectrum is the primary open problem in computational metabolomics. This is typically cast as information retrieval: an unknown spectrum is matched against spectra predicted computationally from a large database of chemical structures. However, current approaches to spectrum prediction model the output space in ways that force a tradeoff between capturing high resolution mass information and tractable learning. We resolve this tradeoff by casting spectrum prediction as a mapping from an input molecular graph to a probability distribution over molecular formulas. We discover that a large corpus of mass spectra can be closely approximated using a fixed vocabulary constituting only 2% of all observed formulas. This enables efficient spectrum prediction using an architecture similar to graph classification - GrAFF-MS - achieving significantly lower prediction error and orders-of-magnitude faster runtime than state-of-the-art methods.

Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.

Supervised learning on molecules has incredible potential to be useful in chemistry, drug discovery, and materials science. Luckily, several promising and closely related neural network models invariant to molecular symmetries have already been described in the literature. These models learn a message passing algorithm and aggregation procedure to compute a function of their entire input graph. At this point, the next step is to find a particularly effective variant of this general approach and apply it to chemical prediction benchmarks until we either solve them or reach the limits of the approach. In this paper, we reformulate existing models into a single common framework we call Message Passing Neural Networks (MPNNs) and explore additional novel variations within this framework. Using MPNNs we demonstrate state of the art results on an important molecular property prediction benchmark; these results are strong enough that we believe future work should focus on datasets with larger molecules or more accurate ground truth labels.

Hit-like molecular generation with therapeutic potential is essential for target-specific drug discovery. However, the field lacks heterogeneous data and unified frameworks for integrating diverse molecular representations. To bridge this gap, we introduce TextOmics, a pioneering benchmark that establishes one-to-one correspondences between omics expressions and molecular textual descriptions. TextOmics provides a heterogeneous dataset that facilitates molecular generation through representations alignment. Built upon this foundation, we propose ToDi, a generative framework that jointly conditions on omics expressions and molecular textual descriptions to produce biologically relevant, chemically valid, hit-like molecules. ToDi leverages two encoders (OmicsEn and TextEn) to capture multi-level biological and semantic associations, and develops conditional diffusion (DiffGen) for controllable generation. Extensive experiments confirm the effectiveness of TextOmics and demonstrate ToDi outperforms existing state-of-the-art approaches, while also showcasing remarkable potential in zero-shot therapeutic molecular generation. Sources are available at: https://github.com/hala-ToDi.

Genetic pathways usually encode molecular mechanisms that can inform targeted interventions. It is often challenging for existing machine learning approaches to jointly model genetic pathways (higher-order features) and variants (atomic features), and present to clinicians interpretable models. In order to build more accurate and better interpretable machine learning models for genetic medicine, we introduce Pathway Augmented Nonnegative Tensor factorization for HighER-order feature learning (PANTHER). PANTHER selects informative genetic pathways that directly encode molecular mechanisms. We apply genetically motivated constrained tensor factorization to group pathways in a way that reflects molecular mechanism interactions. We then train a softmax classifier for disease types using the identified pathway groups. We evaluated PANTHER against multiple state-of-the-art constrained tensor/matrix factorization models, as well as group guided and Bayesian hierarchical models. PANTHER outperforms all state-of-the-art comparison models significantly (p<0.05). Our experiments on large scale Next Generation Sequencing (NGS) and whole-genome genotyping datasets also demonstrated wide applicability of PANTHER. We performed feature analysis in predicting disease types, which suggested insights and benefits of the identified pathway groups.

Pairs of similar compounds that only differ by a small structural modification but exhibit a large difference in their binding affinity for a given target are known as activity cliffs (ACs). It has been hypothesised that quantitative structure-activity relationship (QSAR) models struggle to predict ACs and that ACs thus form a major source of prediction error. However, a study to explore the AC-prediction power of modern QSAR methods and its relationship to general QSAR-prediction performance is lacking. We systematically construct nine distinct QSAR models by combining three molecular representation methods (extended-connectivity fingerprints, physicochemical-descriptor vectors and graph isomorphism networks) with three regression techniques (random forests, k-nearest neighbours and multilayer perceptrons); we then use each resulting model to classify pairs of similar compounds as ACs or non-ACs and to predict the activities of individual molecules in three case studies: dopamine receptor D2, factor Xa, and SARS-CoV-2 main protease. We observe low AC-sensitivity amongst the tested models when the activities of both compounds are unknown, but a substantial increase in AC-sensitivity when the actual activity of one of the compounds is given. Graph isomorphism features are found to be competitive with or superior to classical molecular representations for AC-classification and can thus be employed as baseline AC-prediction models or simple compound-optimisation tools. For general QSAR-prediction, however, extended-connectivity fingerprints still consistently deliver the best performance. Our results provide strong support for the hypothesis that indeed QSAR methods frequently fail to predict ACs. We propose twin-network training for deep learning models as a potential future pathway to increase AC-sensitivity and thus overall QSAR performance.

Generative models are becoming a tool of choice for exploring the molecular space. These models learn on a large training dataset and produce novel molecular structures with similar properties. Generated structures can be utilized for virtual screening or training semi-supervised predictive models in the downstream tasks. While there are plenty of generative models, it is unclear how to compare and rank them. In this work, we introduce a benchmarking platform called Molecular Sets (MOSES) to standardize training and comparison of molecular generative models. MOSES provides a training and testing datasets, and a set of metrics to evaluate the quality and diversity of generated structures. We have implemented and compared several molecular generation models and suggest to use our results as reference points for further advancements in generative chemistry research. The platform and source code are available at https://github.com/molecularsets/moses.

We introduce FragAtlas-62M, a specialized foundation model trained on the largest fragment dataset to date. Built on the complete ZINC-22 fragment subset comprising over 62 million molecules, it achieves unprecedented coverage of fragment chemical space. Our GPT-2 based model (42.7M parameters) generates 99.90% chemically valid fragments. Validation across 12 descriptors and three fingerprint methods shows generated fragments closely match the training distribution (all effect sizes < 0.4). The model retains 53.6% of known ZINC fragments while producing 22% novel structures with practical relevance. We release FragAtlas-62M with training code, preprocessed data, documentation, and model weights to accelerate adoption.

Language models are widely used in chemistry for molecular property prediction and small-molecule generation, yet Natural Products (NPs) remain underexplored despite their importance in drug discovery. To address this gap, we develop NP-specific chemical language models (NPCLMs) by pre-training state-space models (Mamba and Mamba-2) and comparing them with transformer baselines (GPT). Using a dataset of about 1M NPs, we present the first systematic comparison of selective state-space models and transformers for NP-focused tasks, together with eight tokenization strategies including character-level, Atom-in-SMILES (AIS), byte-pair encoding (BPE), and NP-specific BPE. We evaluate molecule generation (validity, uniqueness, novelty) and property prediction (membrane permeability, taste, anti-cancer activity) using MCC and AUC-ROC. Mamba generates 1-2 percent more valid and unique molecules than Mamba-2 and GPT, with fewer long-range dependency errors, while GPT yields slightly more novel structures. For property prediction, Mamba variants outperform GPT by 0.02-0.04 MCC under random splits, while scaffold splits show comparable performance. Results demonstrate that domain-specific pre-training on about 1M NPs can match models trained on datasets over 100 times larger.

Extended-connectivity fingerprints (ECFPs) are a ubiquitous tool in current cheminformatics and molecular machine learning, and one of the most prevalent molecular feature extraction techniques used for chemical prediction. Atom features learned by graph neural networks can be aggregated to compound-level representations using a large spectrum of graph pooling methods; in contrast, sets of detected ECFP substructures are by default transformed into bit vectors using only a simple hash-based folding procedure. We introduce a general mathematical framework for the vectorisation of structural fingerprints via a formal operation called substructure pooling that encompasses hash-based folding, algorithmic substructure-selection, and a wide variety of other potential techniques. We go on to describe Sort & Slice, an easy-to-implement and bit-collision-free alternative to hash-based folding for the pooling of ECFP substructures. Sort & Slice first sorts ECFP substructures according to their relative prevalence in a given set of training compounds and then slices away all but the L most frequent substructures which are subsequently used to generate a binary fingerprint of desired length, L. We computationally compare the performance of hash-based folding, Sort & Slice, and two advanced supervised substructure-selection schemes (filtering and mutual-information maximisation) for ECFP-based molecular property prediction. Our results indicate that, despite its technical simplicity, Sort & Slice robustly (and at times substantially) outperforms traditional hash-based folding as well as the other investigated methods across prediction tasks, data splitting techniques, machine-learning models and ECFP hyperparameters. We thus recommend that Sort & Slice canonically replace hash-based folding as the default substructure-pooling technique to vectorise ECFPs for supervised molecular machine learning.

Large Language Models (LLMs) stand at the forefront of a number of Natural Language Processing (NLP) tasks. Despite the widespread adoption of LLMs in NLP, much of their potential in broader fields remains largely unexplored, and significant limitations persist in their design and implementation. Notably, LLMs struggle with structured data, such as graphs, and often falter when tasked with answering domain-specific questions requiring deep expertise, such as those in biology and chemistry. In this paper, we explore a fundamental question: Can LLMs effectively handle molecule prediction tasks? Rather than pursuing top-tier performance, our goal is to assess how LLMs can contribute to diverse molecule tasks. We identify several classification and regression prediction tasks across six standard molecule datasets. Subsequently, we carefully design a set of prompts to query LLMs on these tasks and compare their performance with existing Machine Learning (ML) models, which include text-based models and those specifically designed for analysing the geometric structure of molecules. Our investigation reveals several key insights: Firstly, LLMs generally lag behind ML models in achieving competitive performance on molecule tasks, particularly when compared to models adept at capturing the geometric structure of molecules, highlighting the constrained ability of LLMs to comprehend graph data. Secondly, LLMs show promise in enhancing the performance of ML models when used collaboratively. Lastly, we engage in a discourse regarding the challenges and promising avenues to harness LLMs for molecule prediction tasks. The code and models are available at https://github.com/zhiqiangzhongddu/LLMaMol.

Text-based foundation models have become an important part of scientific discovery, with molecular foundation models accelerating advancements in material science and molecular design.However, existing models are constrained by closed-vocabulary tokenizers that capture only a fraction of molecular space. In this work, we systematically evaluate 34 tokenizers, including 19 chemistry-specific ones, and reveal significant gaps in their coverage of the SMILES molecular representation. To assess the impact of tokenizer choice, we introduce n-gram language models as a low-cost proxy and validate their effectiveness by pretraining and finetuning 18 RoBERTa-style encoders for molecular property prediction. To overcome the limitations of existing tokenizers, we propose two new tokenizers -- Smirk and Smirk-GPE -- with full coverage of the OpenSMILES specification. The proposed tokenizers systematically integrate nuclear, electronic, and geometric degrees of freedom; facilitating applications in pharmacology, agriculture, biology, and energy storage. Our results highlight the need for open-vocabulary modeling and chemically diverse benchmarks in cheminformatics.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

Automated computational analysis of the vast chemical space is critical for numerous fields of research such as drug discovery and material science. Representation learning techniques have recently been employed with the primary objective of generating compact and informative numerical expressions of complex data. One approach to efficiently learn molecular representations is processing string-based notations of chemicals via natural language processing (NLP) algorithms. Majority of the methods proposed so far utilize SMILES notations for this purpose; however, SMILES is associated with numerous problems related to validity and robustness, which may prevent the model from effectively uncovering the knowledge hidden in the data. In this study, we propose SELFormer, a transformer architecture-based chemical language model that utilizes a 100% valid, compact and expressive notation, SELFIES, as input, in order to learn flexible and high-quality molecular representations. SELFormer is pre-trained on two million drug-like compounds and fine-tuned for diverse molecular property prediction tasks. Our performance evaluation has revealed that, SELFormer outperforms all competing methods, including graph learning-based approaches and SMILES-based chemical language models, on predicting aqueous solubility of molecules and adverse drug reactions. We also visualized molecular representations learned by SELFormer via dimensionality reduction, which indicated that even the pre-trained model can discriminate molecules with differing structural properties. We shared SELFormer as a programmatic tool, together with its datasets and pre-trained models. Overall, our research demonstrates the benefit of using the SELFIES notations in the context of chemical language modeling and opens up new possibilities for the design and discovery of novel drug candidates with desired features.

Predicting drug-target interactions (DTI) is an essential part of the drug discovery process, which is an expensive process in terms of time and cost. Therefore, reducing DTI cost could lead to reduced healthcare costs for a patient. In addition, a precisely learned molecule representation in a DTI model could contribute to developing personalized medicine, which will help many patient cohorts. In this paper, we propose a new molecule representation based on the self-attention mechanism, and a new DTI model using our molecule representation. The experiments show that our DTI model outperforms the state of the art by up to 4.9% points in terms of area under the precision-recall curve. Moreover, a study using the DrugBank database proves that our model effectively lists all known drugs targeting a specific cancer biomarker in the top-30 candidate list.

Accumulated clinical studies show that microbes living in humans interact closely with human hosts, and get involved in modulating drug efficacy and drug toxicity. Microbes have become novel targets for the development of antibacterial agents. Therefore, screening of microbe-drug associations can benefit greatly drug research and development. With the increase of microbial genomic and pharmacological datasets, we are greatly motivated to develop an effective computational method to identify new microbe-drug associations. In this paper, we proposed a novel method, Graph2MDA, to predict microbe-drug associations by using variational graph autoencoder (VGAE). We constructed multi-modal attributed graphs based on multiple features of microbes and drugs, such as molecular structures, microbe genetic sequences, and function annotations. Taking as input the multi-modal attribute graphs, VGAE was trained to learn the informative and interpretable latent representations of each node and the whole graph, and then a deep neural network classifier was used to predict microbe-drug associations. The hyperparameter analysis and model ablation studies showed the sensitivity and robustness of our model. We evaluated our method on three independent datasets and the experimental results showed that our proposed method outperformed six existing state-of-the-art methods. We also explored the meaningness of the learned latent representations of drugs and found that the drugs show obvious clustering patterns that are significantly consistent with drug ATC classification. Moreover, we conducted case studies on two microbes and two drugs and found 75\%-95\% predicted associations have been reported in PubMed literature. Our extensive performance evaluations validated the effectiveness of our proposed method.\

Computational methods that operate on three-dimensional molecular structure have the potential to solve important questions in biology and chemistry. In particular, deep neural networks have gained significant attention, but their widespread adoption in the biomolecular domain has been limited by a lack of either systematic performance benchmarks or a unified toolkit for interacting with molecular data. To address this, we present ATOM3D, a collection of both novel and existing benchmark datasets spanning several key classes of biomolecules. We implement several classes of three-dimensional molecular learning methods for each of these tasks and show that they consistently improve performance relative to methods based on one- and two-dimensional representations. The specific choice of architecture proves to be critical for performance, with three-dimensional convolutional networks excelling at tasks involving complex geometries, graph networks performing well on systems requiring detailed positional information, and the more recently developed equivariant networks showing significant promise. Our results indicate that many molecular problems stand to gain from three-dimensional molecular learning, and that there is potential for improvement on many tasks which remain underexplored. To lower the barrier to entry and facilitate further developments in the field, we also provide a comprehensive suite of tools for dataset processing, model training, and evaluation in our open-source atom3d Python package. All datasets are available for download from https://www.atom3d.ai .

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

Inspired by the success of unsupervised pre-training paradigms, researchers have applied these approaches to DNA pre-training. However, we argue that these approaches alone yield suboptimal results because pure DNA sequences lack sufficient information, since their functions are regulated by genomic profiles like chromatin accessibility. Here, we demonstrate that supervised training for genomic profile prediction serves as a more effective alternative to pure sequence pre-training. Furthermore, considering the multi-species and multi-profile nature of genomic profile prediction, we introduce our Species-Profile Adaptive Collaborative Experts (SPACE) that leverages Mixture of Experts (MoE) to better capture the relationships between DNA sequences across different species and genomic profiles, thereby learning more effective DNA representations. Through extensive experiments across various tasks, our model achieves state-of-the-art performance, establishing that DNA models trained with supervised genomic profiles serve as powerful DNA representation learners. The code is available at https://github.com/ZhuJiwei111/SPACE.

Large language models (LLMs) are introducing a paradigm shift in molecular discovery by enabling text-guided interaction with chemical spaces through natural language, symbolic notations, with emerging extensions to incorporate multi-modal inputs. To advance the new field of LLM for molecular discovery, this survey provides an up-to-date and forward-looking review of the emerging use of LLMs for two central tasks: molecule generation and molecule optimization. Based on our proposed taxonomy for both problems, we analyze representative techniques in each category, highlighting how LLM capabilities are leveraged across different learning settings. In addition, we include the commonly used datasets and evaluation protocols. We conclude by discussing key challenges and future directions, positioning this survey as a resource for researchers working at the intersection of LLMs and molecular science. A continuously updated reading list is available at https://github.com/REAL-Lab-NU/Awesome-LLM-Centric-Molecular-Discovery.

Understanding molecules is key to understanding organisms and driving advances in drug discovery, requiring interdisciplinary knowledge across chemistry and biology. Although large molecular language models have achieved notable success in interpreting molecular structures, their instruction datasets are limited to the specific knowledge from task-oriented datasets and do not fully cover the fundamental characteristics of molecules, hindering their abilities as general-purpose molecular assistants. To address this issue, we propose Mol-LLaMA, a large molecular language model that grasps the general knowledge centered on molecules via multi-modal instruction tuning. To this end, we design key data types that encompass the fundamental features of molecules, incorporating essential knowledge from molecular structures. In addition, to improve understanding of molecular features, we introduce a module that integrates complementary information from different molecular encoders, leveraging the distinct advantages of different molecular representations. Our experimental results demonstrate that Mol-LLaMA is capable of comprehending the general features of molecules and generating relevant responses to users' queries with detailed explanations, implying its potential as a general-purpose assistant for molecular analysis.

We introduce Functional Group-Aware Representations for Small Molecules (FARM), a novel foundation model designed to bridge the gap between SMILES, natural language, and molecular graphs. The key innovation of FARM lies in its functional group-aware tokenization, which incorporates functional group information directly into the representations. This strategic reduction in tokenization granularity in a way that is intentionally interfaced with key drivers of functional properties (i.e., functional groups) enhances the model's understanding of chemical language, expands the chemical lexicon, more effectively bridging SMILES and natural language, and ultimately advances the model's capacity to predict molecular properties. FARM also represents molecules from two perspectives: by using masked language modeling to capture atom-level features and by employing graph neural networks to encode the whole molecule topology. By leveraging contrastive learning, FARM aligns these two views of representations into a unified molecular embedding. We rigorously evaluate FARM on the MoleculeNet dataset, where it achieves state-of-the-art performance on 10 out of 12 tasks. These results highlight FARM's potential to improve molecular representation learning, with promising applications in drug discovery and pharmaceutical research.

Recent advances in molecular representation learning have produced highly effective encodings of molecules for numerous cheminformatics and bioinformatics tasks. However, extracting general chemical insight while balancing predictive accuracy, interpretability, and computational efficiency remains a major challenge. In this work, we introduce a novel Graph Neural Network (GNN) architecture that combines compressed higher-order topological signals with standard molecular features. Our approach captures global geometric information while preserving computational tractability and human-interpretable structure. We evaluate our model across a range of benchmarks, from small-molecule datasets to complex material datasets, and demonstrate superior performance using a parameter-efficient architecture. We achieve the best performing results in both accuracy and robustness across almost all benchmarks. We open source all code All code and results can be found on Github https://github.com/rahulkhorana/TFC-PACT-Net.

The application of deep learning methods, particularly foundation models, in biological research has surged in recent years. These models can be text-based or trained on underlying biological data, especially omics data of various types. However, comparing the performance of these models consistently has proven to be a challenge due to differences in training data and downstream tasks. To tackle this problem, we developed an architecture-agnostic benchmarking approach that, instead of evaluating the models directly, leverages entity representation vectors from each model and trains simple predictive models for each benchmarking task. This ensures that all types of models are evaluated using the same input and output types. Here we focus on gene properties collected from professionally curated bioinformatics databases. These gene properties are categorized into five major groups: genomic properties, regulatory functions, localization, biological processes, and protein properties. Overall, we define hundreds of tasks based on these databases, which include binary, multi-label, and multi-class classification tasks. We apply these benchmark tasks to evaluate expression-based models, large language models, protein language models, DNA-based models, and traditional baselines. Our findings suggest that text-based models and protein language models generally outperform expression-based models in genomic properties and regulatory functions tasks, whereas expression-based models demonstrate superior performance in localization tasks. These results should aid in the development of more informed artificial intelligence strategies for biological understanding and therapeutic discovery. To ensure the reproducibility and transparency of our findings, we have made the source code and benchmark data publicly accessible for further investigation and expansion at github.com/BiomedSciAI/gene-benchmark.

Spatial transcriptomics (ST) provides spatially resolved measurements of gene expression, enabling characterization of the molecular landscape of human tissue beyond histological assessment as well as localized readouts that can be aligned with morphology. Concurrently, the success of multimodal foundation models that integrate vision with complementary modalities suggests that morphomolecular coupling between local expression and morphology can be systematically used to improve histological representations themselves. We introduce Spatial Expression-Aligned Learning (SEAL), a vision-omics self-supervised learning framework that infuses localized molecular information into pathology vision encoders. Rather than training new encoders from scratch, SEAL is designed as a parameter-efficient vision-omics finetuning method that can be flexibly applied to widely used pathology foundation models. We instantiate SEAL by training on over 700,000 paired gene expression spot-tissue region examples spanning tumor and normal samples from 14 organs. Tested across 38 slide-level and 15 patch-level downstream tasks, SEAL provides a drop-in replacement for pathology foundation models that consistently improves performance over widely used vision-only and ST prediction baselines on slide-level molecular status, pathway activity, and treatment response prediction, as well as patch-level gene expression prediction tasks. Additionally, SEAL encoders exhibit robust domain generalization on out-of-distribution evaluations and enable new cross-modal capabilities such as gene-to-image retrieval. Our work proposes a general framework for ST-guided finetuning of pathology foundation models, showing that augmenting existing models with localized molecular supervision is an effective and practical step for improving visual representations and expanding their cross-modal utility.

This paper introduces M^{3}-20M, a large-scale Multi-Modal Molecular dataset that contains over 20 million molecules. Designed to support AI-driven drug design and discovery, M^{3}-20M is 71 times more in the number of molecules than the largest existing dataset, providing an unprecedented scale that can highly benefit training or fine-tuning large (language) models with superior performance for drug design and discovery. This dataset integrates one-dimensional SMILES, two-dimensional molecular graphs, three-dimensional molecular structures, physicochemical properties, and textual descriptions collected through web crawling and generated by using GPT-3.5, offering a comprehensive view of each molecule. To demonstrate the power of M^{3}-20M in drug design and discovery, we conduct extensive experiments on two key tasks: molecule generation and molecular property prediction, using large language models including GLM4, GPT-3.5, and GPT-4. Our experimental results show that M^{3}-20M can significantly boost model performance in both tasks. Specifically, it enables the models to generate more diverse and valid molecular structures and achieve higher property prediction accuracy than the existing single-modal datasets, which validates the value and potential of M^{3}-20M in supporting AI-driven drug design and discovery. The dataset is available at https://github.com/bz99bz/M-3.

Multi-omics research has enhanced our understanding of cancer heterogeneity and progression. Investigating molecular data through multi-omics approaches is crucial for unraveling the complex biological mechanisms underlying cancer, thereby enabling effective diagnosis, treatment, and prevention strategies. However, predicting patient outcomes through integration of all available multi-omics data is an under-study research direction. Here, we present SeNMo (Self-normalizing Network for Multi-omics), a deep neural network trained on multi-omics data across 33 cancer types. SeNMo is efficient in handling multi-omics data characterized by high-width (many features) and low-length (fewer samples) attributes. We trained SeNMo for the task of overall survival using pan-cancer data involving 33 cancer sites from Genomics Data Commons (GDC). The training data includes gene expression, DNA methylation, miRNA expression, DNA mutations, protein expression modalities, and clinical data. We evaluated the model's performance in predicting overall survival using concordance index (C-Index). SeNMo performed consistently well in training regime, with the validation C-Index of 0.76 on GDC's public data. In the testing regime, SeNMo performed with a C-Index of 0.758 on a held-out test set. The model showed an average accuracy of 99.8% on the task of classifying the primary cancer type on the pan-cancer test cohort. SeNMo proved to be a mini-foundation model for multi-omics oncology data because it demonstrated robust performance, and adaptability not only across molecular data types but also on the classification task of predicting the primary cancer type of patients. SeNMo can be further scaled to any cancer site and molecular data type. We believe SeNMo and similar models are poised to transform the oncology landscape, offering hope for more effective, efficient, and patient-centric cancer care.

Molecular property prediction is crucial for drug discovery and materials science, yet existing approaches suffer from limited interpretability, poor cross-task generalization, and lack of chemical reasoning capabilities. Traditional machine learning models struggle with task transferability, while specialized molecular language models provide little insight into their decision-making processes. To address these limitations, we propose MPPReasoner, a multimodal large language model that incorporates chemical reasoning for molecular property prediction. Our approach, built upon Qwen2.5-VL-7B-Instruct, integrates molecular images with SMILES strings to enable comprehensive molecular understanding. We develop a two-stage training strategy: supervised fine-tuning (SFT) using 16,000 high-quality reasoning trajectories generated through expert knowledge and multiple teacher models, followed by Reinforcement Learning from Principle-Guided Rewards (RLPGR). RLPGR employs verifiable, rule-based rewards that systematically evaluate chemical principle application, molecular structure analysis, and logical consistency through computational verification. Extensive experiments across 8 datasets demonstrate significant performance improvements, with MPPReasoner outperforming the best baselines by 7.91\% and 4.53\% on in-distribution and out-of-distribution tasks respectively. MPPReasoner exhibits exceptional cross-task generalization and generates chemically sound reasoning paths that provide valuable insights into molecular property analysis, substantially enhancing both interpretability and practical utility for chemists. Code is available at https://anonymous.4open.science/r/MPPReasoner-12687.

Predicting ATP-Protein Binding sites in genes is of great significance in the field of Biology and Medicine. The majority of research in this field has been conducted through time- and resource-intensive 'wet experiments' in laboratories. Over the years, researchers have been investigating computational methods computational methods to accomplish the same goals, utilising the strength of advanced Deep Learning and NLP algorithms. In this paper, we propose to develop methods to classify ATP-Protein binding sites. We conducted various experiments mainly using PSSMs and several word embeddings as features. We used 2D CNNs and LightGBM classifiers as our chief Deep Learning Algorithms. The MP3Vec and BERT models have also been subjected to testing in our study. The outcomes of our experiments demonstrated improvement over the state-of-the-art benchmarks.

The drug development pipeline for a new compound can last 10-20 years and cost over 10 billion. Drug repurposing offers a more time- and cost-effective alternative. Computational approaches based on biomedical knowledge graph representations have recently yielded new drug repurposing hypotheses. In this study, we present a novel, disease-specific hypergraph representation learning technique to derive contextual embeddings of biological pathways of various lengths but that all start at any given drug and all end at the disease of interest. Further, we extend this method to multi-disease hypergraphs. To determine the repurposing potential of each of the 1,522 drugs, we derive drug-specific distributions of cosine similarity values and ultimately consider the median for ranking. Cosine similarity values are computed between (1) all biological pathways starting at the considered drug and ending at the disease of interest and (2) all biological pathways starting at drugs currently prescribed against that disease and ending at the disease of interest. We illustrate our approach with Alzheimer's disease (AD) and two of its risk factors: hypertension (HTN) and type 2 diabetes (T2D). We compare each drug's rank across four hypergraph settings (single- or multi-disease): AD only, AD + HTN, AD + T2D, and AD + HTN + T2D. Notably, our framework led to the identification of two promising drugs whose repurposing potential was significantly higher in hypergraphs combining two diseases: dapagliflozin (antidiabetic; moved up, from top 32% to top 7%, across all considered drugs) and debrisoquine (antihypertensive; moved up, from top 76% to top 23%). Our approach serves as a hypothesis generation tool, to be paired with a validation pipeline relying on laboratory experiments and semi-automated parsing of the biomedical literature.

Cancer is the second leading cause of death, with chemotherapy as one of the primary forms of treatment. As a result, researchers are turning to drug combination therapy to decrease drug resistance and increase efficacy. Current methods of drug combination screening, such as in vivo and in vitro, are inefficient due to stark time and monetary costs. In silico methods have become increasingly important for screening drugs, but current methods are inaccurate and generalize poorly to unseen anticancer drugs. In this paper, I employ a geometric deep-learning model utilizing a graph attention network that is equivariant to 3D rotations, translations, and reflections with structural motifs. Additionally, the gene expression of cancer cell lines is utilized to classify synergistic drug combinations specific to each cell line. I compared the proposed geometric deep learning framework to current state-of-the-art (SOTA) methods, and the proposed model architecture achieved greater performance on all 12 benchmark tasks performed on the DrugComb dataset. Specifically, the proposed framework outperformed other SOTA methods by an accuracy difference greater than 28%. Based on these results, I believe that the equivariant graph attention network's capability of learning geometric data accounts for the large performance improvements. The model's ability to generalize to foreign drugs is thought to be due to the structural motifs providing a better representation of the molecule. Overall, I believe that the proposed equivariant geometric deep learning framework serves as an effective tool for virtually screening anticancer drug combinations for further validation in a wet lab environment. The code for this work is made available online at: https://github.com/WeToTheMoon/EGAT_DrugSynergy.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

Traditional AI methods often rely on task-specific model designs and training, which constrain both the scalability of model size and generalization across different tasks. Here, we introduce ChemFM, a large foundation model specifically developed for chemicals. By conducting a series of scaling experiments, we identify UniChem as the informative molecular database for pre-training the foundation model. ChemFM comprises 3 billion parameters and is pre-trained on 178 million molecules using self-supervised causal language modeling to extract generalizable molecular representations. This model can be adapted to diverse downstream chemical applications using either full-parameter or parameter-efficient fine-tuning methods. ChemFM consistently outperforms state-of-the-art task-specific AI models across all tested tasks. Notably, it achieves up to 67.48% performance improvement across 34 property prediction benchmarks, up to 33.80% reduction in mean average deviation between conditioned and actual properties of generated molecules in conditional molecular generation tasks, and up to 3.7% top-1 accuracy improvement across 4 reaction prediction datasets. Moreover, ChemFM demonstrates its superior performance in predicting antibiotic activity and cytotoxicity, highlighting its potential to advance the discovery of novel antibiotics. Furthermore, we demonstrate that, as a foundation model, ChemFM exhibits strong data efficiency, requiring significantly fewer labeled training samples to achieve state-of-the-art performance. We anticipate that ChemFM will significantly advance chemistry research by providing a foundation model capable of effectively generalizing across a broad range of tasks with minimal additional training.

While machine learning on graphs has demonstrated promise in drug design and molecular property prediction, significant benchmarking challenges hinder its further progress and relevance. Current benchmarking practices often lack focus on transformative, real-world applications, favoring narrow domains like two-dimensional molecular graphs over broader, impactful areas such as combinatorial optimization, relational databases, or chip design. Additionally, many benchmark datasets poorly represent the underlying data, leading to inadequate abstractions and misaligned use cases. Fragmented evaluations and an excessive focus on accuracy further exacerbate these issues, incentivizing overfitting rather than fostering generalizable insights. These limitations have prevented the development of truly useful graph foundation models. This position paper calls for a paradigm shift toward more meaningful benchmarks, rigorous evaluation protocols, and stronger collaboration with domain experts to drive impactful and reliable advances in graph learning research, unlocking the potential of graph learning.

RNA is a vital biomolecule with numerous roles and functions within cells, and interest in targeting it for therapeutic purposes has grown significantly in recent years. However, fully understanding and predicting RNA behavior, particularly for applications in drug discovery, remains a challenge due to the complexity of RNA structures and interactions. While foundational models in biology have demonstrated success in modeling several biomolecules, especially proteins, achieving similar breakthroughs for RNA has proven more difficult. Current RNA models have yet to match the performance observed in the protein domain, leaving an important gap in computational biology. In this work, we present ChaRNABERT, a suite of sample and parameter-efficient RNA foundational models, that through a learnable tokenization process, are able to reach state-of-the-art performance on several tasks in established benchmarks. We extend its testing in relevant downstream tasks such as RNA-protein and aptamer-protein interaction prediction. Weights and inference code for ChaRNABERT-8M will be provided for academic research use. The other models will be available upon request.

Complex gene interactions play a significant role in cancer progression, driving cellular behaviors that contribute to tumor growth, invasion, and metastasis. Gene co-expression networks model the functional connectivity between genes under various biological conditions. Understanding the system-level evolution of these networks in cancer is critical for elucidating disease mechanisms and informing the development of targeted therapies. While previous studies have primarily focused on structural differences between cancer and normal cell co-expression networks, this study applies graph frequency analysis to cancer transcriptomic signals defined on gene co-expression networks, highlighting the graph spectral characteristics of cancer systems. Using a range of graph frequency filters, we showed that cancer cells display distinctive patterns in the graph frequency content of their gene transcriptomic signals, effectively distinguishing between cancer types and stages. The transformation of the original gene feature space into the graph spectral space captured more intricate cancer properties, as validated by significantly higher F-statistic scores for graph frequency-filtered gene features compared to those in the original space.

Diversity is an important criterion for many areas of machine learning (ML), including generative modeling and dataset curation. Yet little work has gone into understanding, formalizing, and measuring diversity in ML. In this paper, we address the diversity evaluation problem by proposing the Vendi Score, which connects and extends ideas from ecology and quantum statistical mechanics to ML. The Vendi Score is defined as the exponential of the Shannon entropy of the eigenvalues of a similarity matrix. This matrix is induced by a user-defined similarity function applied to the sample to be evaluated for diversity. In taking a similarity function as input, the Vendi Score enables its user to specify any desired form of diversity. Importantly, unlike many existing metrics in ML, the Vendi Score doesn't require a reference dataset or distribution over samples or labels, it is therefore general and applicable to any generative model, decoding algorithm, and dataset from any domain where similarity can be defined. We showcased the Vendi Score on molecular generative modeling, a domain where diversity plays an important role in enabling the discovery of novel molecules. We found that the Vendi Score addresses shortcomings of the current diversity metric of choice in that domain. We also applied the Vendi Score to generative models of images and decoding algorithms of text and found it confirms known results about diversity in those domains. Furthermore, we used the Vendi Score to measure mode collapse, a known limitation of generative adversarial networks (GANs). In particular, the Vendi Score revealed that even GANs that capture all the modes of a labeled dataset can be less diverse than the original dataset. Finally, the interpretability of the Vendi Score allowed us to diagnose several benchmark ML datasets for diversity, opening the door for diversity-informed data augmentation.

The discovery of novel materials and functional molecules can help to solve some of society's most urgent challenges, ranging from efficient energy harvesting and storage to uncovering novel pharmaceutical drug candidates. Traditionally matter engineering -- generally denoted as inverse design -- was based massively on human intuition and high-throughput virtual screening. The last few years have seen the emergence of significant interest in computer-inspired designs based on evolutionary or deep learning methods. The major challenge here is that the standard strings molecular representation SMILES shows substantial weaknesses in that task because large fractions of strings do not correspond to valid molecules. Here, we solve this problem at a fundamental level and introduce SELFIES (SELF-referencIng Embedded Strings), a string-based representation of molecules which is 100\% robust. Every SELFIES string corresponds to a valid molecule, and SELFIES can represent every molecule. SELFIES can be directly applied in arbitrary machine learning models without the adaptation of the models; each of the generated molecule candidates is valid. In our experiments, the model's internal memory stores two orders of magnitude more diverse molecules than a similar test with SMILES. Furthermore, as all molecules are valid, it allows for explanation and interpretation of the internal working of the generative models.

Deep learning in computational biochemistry has traditionally focused on molecular graphs neural representations; however, recent advances in language models highlight how much scientific knowledge is encoded in text. To bridge these two modalities, we investigate how molecular property information can be transferred from natural language to graph representations. We study property prediction performance gains after using contrastive learning to align neural graph representations with representations of textual descriptions of their characteristics. We implement neural relevance scoring strategies to improve text retrieval, introduce a novel chemically-valid molecular graph augmentation strategy inspired by organic reactions, and demonstrate improved performance on downstream MoleculeNet property classification tasks. We achieve a +4.26% AUROC gain versus models pre-trained on the graph modality alone, and a +1.54% gain compared to recently proposed molecular graph/text contrastively trained MoMu model (Su et al. 2022).

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genomes generation tasks demonstrates DNAGPT's superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.

The annotation (assigning structural chemical identities) of MS/MS spectra remains a significant challenge due to the enormous molecular diversity in biological samples and the limited scope of reference databases. Currently, the vast majority of spectral measurements remain in the "dark chemical space" without structural annotations. To improve annotation, we propose MADGEN (Mass-spec Attends to De Novo Molecular GENeration), a scaffold-based method for de novo molecular structure generation guided by mass spectrometry data. MADGEN operates in two stages: scaffold retrieval and spectra-conditioned molecular generation starting with the scaffold. In the first stage, given an MS/MS spectrum, we formulate scaffold retrieval as a ranking problem and employ contrastive learning to align mass spectra with candidate molecular scaffolds. In the second stage, starting from the retrieved scaffold, we employ the MS/MS spectrum to guide an attention-based generative model to generate the final molecule. Our approach constrains the molecular generation search space, reducing its complexity and improving generation accuracy. We evaluate MADGEN on three datasets (NIST23, CANOPUS, and MassSpecGym) and evaluate MADGEN's performance with a predictive scaffold retriever and with an oracle retriever. We demonstrate the effectiveness of using attention to integrate spectral information throughout the generation process to achieve strong results with the oracle retriever.

Graph neural networks (GNNs) have been used extensively for addressing problems in drug design and discovery. Both ligand and target molecules are represented as graphs with node and edge features encoding information about atomic elements and bonds respectively. Although existing deep learning models perform remarkably well at predicting physicochemical properties and binding affinities, the generation of new molecules with optimized properties remains challenging. Inherently, most GNNs perform poorly in whole-graph representation due to the limitations of the message-passing paradigm. Furthermore, step-by-step graph generation frameworks that use reinforcement learning or other sequential processing can be slow and result in a high proportion of invalid molecules with substantial post-processing needed in order to satisfy the principles of stoichiometry. To address these issues, we propose a representation-first approach to molecular graph generation. We guide the latent representation of an autoencoder by capturing graph structure information with the geometric scattering transform and apply penalties that structure the representation also by molecular properties. We show that this highly structured latent space can be directly used for molecular graph generation by the use of a GAN. We demonstrate that our architecture learns meaningful representations of drug datasets and provides a platform for goal-directed drug synthesis.

Most of the current transformer-based chemical language models are pre-trained on millions to billions of molecules. However, the improvement from such scaling in dataset size is not confidently linked to improved molecular property prediction. The aim of this study is to investigate and overcome some of the limitations of transformer models in predicting molecular properties. Specifically, we examine the impact of pre-training dataset size and diversity on the performance of transformer models and investigate the use of domain adaptation as a technique for improving model performance. First, our findings indicate that increasing pretraining dataset size beyond 400K molecules from the GuacaMol dataset does not result in a significant improvement on four ADME endpoints, namely, solubility, permeability, microsomal stability, and plasma protein binding. Second, our results demonstrate that using domain adaptation by further training the transformer model on a small set of domain-relevant molecules, i.e., a few hundred to a few thousand, using multi-task regression of physicochemical properties was sufficient to significantly improve performance for three out of the four investigated ADME endpoints (P-value < 0.001). Finally, we observe that a model pre-trained on 400K molecules and domain adopted on a few hundred/thousand molecules performs similarly (P-value > 0.05) to more complicated transformer models like MolBERT(pre-trained on 1.3M molecules) and MolFormer (pre-trained on 100M molecules). A comparison to a random forest model trained on basic physicochemical properties showed similar performance to the examined transformer models. We believe that current transformer models can be improved through further systematic analysis of pre-training and downstream data, pre-training objectives, and scaling laws, ultimately leading to better and more helpful models.

While various models and computational tools have been proposed for structure and property analysis of molecules, generating molecules that conform to all desired structures and properties remains a challenge. Here, we introduce a multi-constraint molecular generation large language model, TSMMG, which, akin to a student, incorporates knowledge from various small models and tools, namely, the 'teachers'. To train TSMMG, we construct a large set of text-molecule pairs by extracting molecular knowledge from these 'teachers', enabling it to generate novel molecules that conform to the descriptions through various text prompts. We experimentally show that TSMMG remarkably performs in generating molecules meeting complex, natural language-described property requirements across two-, three-, and four-constraint tasks, with an average molecular validity of over 99% and success ratio of 82.58%, 68.03%, and 67.48%, respectively. The model also exhibits adaptability through zero-shot testing, creating molecules that satisfy combinations of properties that have not been encountered. It can comprehend text inputs with various language styles, extending beyond the confines of outlined prompts, as confirmed through empirical validation. Additionally, the knowledge distillation feature of TSMMG contributes to the continuous enhancement of small models, while the innovative approach to dataset construction effectively addresses the issues of data scarcity and quality, which positions TSMMG as a promising tool in the domains of drug discovery and materials science.

The sparsity of labelled data is an obstacle to the development of Relation Extraction models and the completion of databases in various biomedical areas. While being of high interest in drug-discovery, the natural-products literature, reporting the identification of potential bioactive compounds from organisms, is a concrete example of such an overlooked topic. To mark the start of this new task, we created the first curated evaluation dataset and extracted literature items from the LOTUS database to build training sets. To this end, we developed a new sampler inspired by diversity metrics in ecology, named Greedy Maximum Entropy sampler, or GME-sampler (https://github.com/idiap/gme-sampler). The strategic optimization of both balance and diversity of the selected items in the evaluation set is important given the resource-intensive nature of manual curation. After quantifying the noise in the training set, in the form of discrepancies between the input abstracts text and the expected output labels, we explored different strategies accordingly. Framing the task as an end-to-end Relation Extraction, we evaluated the performance of standard fine-tuning as a generative task and few-shot learning with open Large Language Models (LLaMA 7B-65B). In addition to their evaluation in few-shot settings, we explore the potential of open Large Language Models (Vicuna-13B) as synthetic data generator and propose a new workflow for this purpose. All evaluated models exhibited substantial improvements when fine-tuned on synthetic abstracts rather than the original noisy data. We provide our best performing (f1-score=59.0) BioGPT-Large model for end-to-end RE of natural-products relationships along with all the generated synthetic data and the evaluation dataset. See more details at https://github.com/idiap/abroad-re.

The challenge of replicating research results has posed a significant impediment to the field of molecular biology. The advent of modern intelligent systems has led to notable progress in various domains. Consequently, we embarked on an investigation of intelligent monitoring systems as a means of tackling the issue of the reproducibility crisis. Specifically, we first curate a comprehensive multimodal dataset, named ProBio, as an initial step towards this objective. This dataset comprises fine-grained hierarchical annotations intended for the purpose of studying activity understanding in BioLab. Next, we devise two challenging benchmarks, transparent solution tracking and multimodal action recognition, to emphasize the unique characteristics and difficulties associated with activity understanding in BioLab settings. Finally, we provide a thorough experimental evaluation of contemporary video understanding models and highlight their limitations in this specialized domain to identify potential avenues for future research. We hope ProBio with associated benchmarks may garner increased focus on modern AI techniques in the realm of molecular biology.

We present a perspective on molecular machine learning (ML) in the field of chemical process engineering. Recently, molecular ML has demonstrated great potential in (i) providing highly accurate predictions for properties of pure components and their mixtures, and (ii) exploring the chemical space for new molecular structures. We review current state-of-the-art molecular ML models and discuss research directions that promise further advancements. This includes ML methods, such as graph neural networks and transformers, which can be further advanced through the incorporation of physicochemical knowledge in a hybrid or physics-informed fashion. Then, we consider leveraging molecular ML at the chemical process scale, which is highly desirable yet rather unexplored. We discuss how molecular ML can be integrated into process design and optimization formulations, promising to accelerate the identification of novel molecules and processes. To this end, it will be essential to create molecule and process design benchmarks and practically validate proposed candidates, possibly in collaboration with the chemical industry.

During times of increasing antibiotic resistance and the spread of infectious diseases like COVID-19, it is important to classify genes related to antibiotic resistance. As natural language processing has advanced with transformer-based language models, many language models that learn characteristics of nucleotide sequences have also emerged. These models show good performance in classifying various features of nucleotide sequences. When classifying nucleotide sequences, not only the sequence itself, but also various background knowledge is utilized. In this study, we use not only a nucleotide sequence-based language model but also a text language model based on PubMed articles to reflect more biological background knowledge in the model. We propose a method to fine-tune the nucleotide sequence language model and the text language model based on various databases of antibiotic resistance genes. We also propose an LLM-based augmentation technique to supplement the data and an ensemble method to effectively combine the two models. We also propose a benchmark for evaluating the model. Our method achieved better performance than the nucleotide sequence language model in the drug resistance class prediction.

Recent advancements in large language models have opened new possibilities for generative molecular drug design. We present Chemlactica and Chemma, two language models fine-tuned on a novel corpus of 110M molecules with computed properties, totaling 40B tokens. These models demonstrate strong performance in generating molecules with specified properties and predicting new molecular characteristics from limited samples. We introduce a novel optimization algorithm that leverages our language models to optimize molecules for arbitrary properties given limited access to a black box oracle. Our approach combines ideas from genetic algorithms, rejection sampling, and prompt optimization. It achieves state-of-the-art performance on multiple molecular optimization benchmarks, including an 8% improvement on Practical Molecular Optimization compared to previous methods. We publicly release the training corpus, the language models and the optimization algorithm.

Chemical representation learning has gained increasing interest due to the limited availability of supervised data in fields such as drug and materials design. This interest particularly extends to chemical language representation learning, which involves pre-training Transformers on SMILES sequences -- textual descriptors of molecules. Despite its success in molecular property prediction, current practices often lead to overfitting and limited scalability due to early convergence. In this paper, we introduce a novel chemical language representation learning framework, called MolTRES, to address these issues. MolTRES incorporates generator-discriminator training, allowing the model to learn from more challenging examples that require structural understanding. In addition, we enrich molecular representations by transferring knowledge from scientific literature by integrating external materials embedding. Experimental results show that our model outperforms existing state-of-the-art models on popular molecular property prediction tasks.

Molecular representation learning contributes to multiple downstream tasks such as molecular property prediction and drug design. To properly represent molecules, graph contrastive learning is a promising paradigm as it utilizes self-supervision signals and has no requirements for human annotations. However, prior works fail to incorporate fundamental domain knowledge into graph semantics and thus ignore the correlations between atoms that have common attributes but are not directly connected by bonds. To address these issues, we construct a Chemical Element Knowledge Graph (KG) to summarize microscopic associations between elements and propose a novel Knowledge-enhanced Contrastive Learning (KCL) framework for molecular representation learning. KCL framework consists of three modules. The first module, knowledge-guided graph augmentation, augments the original molecular graph based on the Chemical Element KG. The second module, knowledge-aware graph representation, extracts molecular representations with a common graph encoder for the original molecular graph and a Knowledge-aware Message Passing Neural Network (KMPNN) to encode complex information in the augmented molecular graph. The final module is a contrastive objective, where we maximize agreement between these two views of molecular graphs. Extensive experiments demonstrated that KCL obtained superior performances against state-of-the-art baselines on eight molecular datasets. Visualization experiments properly interpret what KCL has learned from atoms and attributes in the augmented molecular graphs. Our codes and data are available at https://github.com/ZJU-Fangyin/KCL.

Molecular knowledge resides within three different modalities of information sources: molecular structures, biomedical documents, and knowledge bases. Effective incorporation of molecular knowledge from these modalities holds paramount significance in facilitating biomedical research. However, existing multimodal molecular foundation models exhibit limitations in capturing intricate connections between molecular structures and texts, and more importantly, none of them attempt to leverage a wealth of molecular expertise derived from knowledge graphs. In this study, we introduce MolFM, a multimodal molecular foundation model designed to facilitate joint representation learning from molecular structures, biomedical texts, and knowledge graphs. We propose cross-modal attention between atoms of molecular structures, neighbors of molecule entities and semantically related texts to facilitate cross-modal comprehension. We provide theoretical analysis that our cross-modal pre-training captures local and global molecular knowledge by minimizing the distance in the feature space between different modalities of the same molecule, as well as molecules sharing similar structures or functions. MolFM achieves state-of-the-art performance on various downstream tasks. On cross-modal retrieval, MolFM outperforms existing models with 12.13% and 5.04% absolute gains under the zero-shot and fine-tuning settings, respectively. Furthermore, qualitative analysis showcases MolFM's implicit ability to provide grounding from molecular substructures and knowledge graphs. Code and models are available on https://github.com/BioFM/OpenBioMed.

Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ breast cancer, which is costly, tissue destructive, requires specialized platforms and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA-sequencing techniques to predict the expression of 138 genes (incorporated from six commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E) stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n=335). We demonstrate successful gene prediction on a held-out test set (n = 160, corr = 0.82 across patients, corr = 0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n = 498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index = 0.56, hazard ratio = 2.16 (95% CI 1.12-3.06), p < 5 x 10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index = 0.65, hazard ratio = 1.85 (95% CI 1.30-2.68), p < 5 x 10-3).

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

Accurate prediction of molecular properties is essential in drug discovery and related fields. However, existing graph neural networks (GNNs) often struggle to simultaneously capture both local and global molecular structures. In this work, we propose a Multi-Level Fusion Graph Neural Network (MLFGNN) that integrates Graph Attention Networks and a novel Graph Transformer to jointly model local and global dependencies. In addition, we incorporate molecular fingerprints as a complementary modality and introduce a mechanism of interaction between attention to adaptively fuse information across representations. Extensive experiments on multiple benchmark datasets demonstrate that MLFGNN consistently outperforms state-of-the-art methods in both classification and regression tasks. Interpretability analysis further reveals that the model effectively captures task-relevant chemical patterns, supporting the usefulness of multi-level and multi-modal fusion in molecular representation learning.

Large Language Models (LLMs) with strong abilities in natural language processing tasks have emerged and have been rapidly applied in various kinds of areas such as science, finance and software engineering. However, the capability of LLMs to advance the field of chemistry remains unclear. In this paper,we establish a comprehensive benchmark containing 8 practical chemistry tasks, including 1) name prediction, 2) property prediction, 3) yield prediction, 4) reaction prediction, 5) retrosynthesis (prediction of reactants from products), 6)text-based molecule design, 7) molecule captioning, and 8) reagent selection. Our analysis draws on widely recognized datasets including BBBP, Tox21, PubChem, USPTO, and ChEBI, facilitating a broad exploration of the capacities of LLMs within the context of practical chemistry. Three GPT models (GPT-4, GPT-3.5,and Davinci-003) are evaluated for each chemistry task in zero-shot and few-shot in-context learning settings with carefully selected demonstration examples and specially crafted prompts. The key results of our investigation are 1) GPT-4 outperforms the other two models among the three evaluated; 2) GPT models exhibit less competitive performance in tasks demanding precise understanding of molecular SMILES representation, such as reaction prediction and retrosynthesis;3) GPT models demonstrate strong capabilities in text-related explanation tasks such as molecule captioning; and 4) GPT models exhibit comparable or better performance to classical machine learning models when applied to chemical problems that can be transformed into classification or ranking tasks, such as property prediction, and yield prediction.

Despite their ability to understand chemical knowledge, large language models (LLMs) remain limited in their capacity to propose novel molecules with desired functions (e.g., drug-like properties). In addition, the molecules that LLMs propose can often be challenging to make, and are almost never compatible with automated synthesis approaches. To better enable the discovery of functional small molecules, LLMs need to learn a new molecular language that is more effective in predicting properties and inherently synced with automated synthesis technology. Current molecule LLMs are limited by representing molecules based on atoms. In this paper, we argue that just like tokenizing texts into meaning-bearing (sub-)word tokens instead of characters, molecules should be tokenized at the level of functional building blocks, i.e., parts of molecules that bring unique functions and serve as effective building blocks for real-world automated laboratory synthesis. This motivates us to propose mCLM, a modular Chemical-Language Model that comprises a bilingual language model that understands both natural language descriptions of functions and molecular blocks. mCLM front-loads synthesizability considerations while improving the predicted functions of molecules in a principled manner. mCLM, with only 3B parameters, achieves improvements in synthetic accessibility relative to 7 other leading generative AI methods including GPT-5. When tested on 122 out-of-distribution medicines using only building blocks/tokens that are compatible with automated modular synthesis, mCLM outperforms all baselines in property scores and synthetic accessibility. mCLM can also reason on multiple functions and iteratively self-improve to rescue drug candidates that failed late in clinical trials ("fallen angels").

We present Connection-Aware Motif Sequencing (CamS), a graph-to-sequence representation that enables decoder-only Transformers to learn molecular graphs via standard next-token prediction (NTP). For molecular property prediction, SMILES-based NTP scales well but lacks explicit topology, whereas graph-native masked modeling captures connectivity but risks disrupting the pivotal chemical details (e.g., activity cliffs). CamS bridges this gap by serializing molecular graphs into structure-rich causal sequences. CamS first mines data-driven connection-aware motifs. It then serializes motifs via scaffold-rooted breadth-first search (BFS) to establish a stable core-to-periphery order. Crucially, CamS enables hierarchical modeling by concatenating sequences from fine to coarse motif scales, allowing the model to condition global scaffolds on dense, uncorrupted local structural evidence. We instantiate CamS-LLaMA by pre-training a vanilla LLaMA backbone on CamS sequences. It achieves state-of-the-art performance on MoleculeNet and the activity-cliff benchmark MoleculeACE, outperforming both SMILES-based language models and strong graph baselines. Interpretability analysis confirms that our multi-scale causal serialization effectively drives attention toward cliff-determining differences.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

Models based on machine learning can enable accurate and fast molecular property predictions, which is of interest in drug discovery and material design. Various supervised machine learning models have demonstrated promising performance, but the vast chemical space and the limited availability of property labels make supervised learning challenging. Recently, unsupervised transformer-based language models pretrained on a large unlabelled corpus have produced state-of-the-art results in many downstream natural language processing tasks. Inspired by this development, we present molecular embeddings obtained by training an efficient transformer encoder model, MoLFormer, which uses rotary positional embeddings. This model employs a linear attention mechanism, coupled with highly distributed training, on SMILES sequences of 1.1 billion unlabelled molecules from the PubChem and ZINC datasets. We show that the learned molecular representation outperforms existing baselines, including supervised and self-supervised graph neural networks and language models, on several downstream tasks from ten benchmark datasets. They perform competitively on two others. Further analyses, specifically through the lens of attention, demonstrate that MoLFormer trained on chemical SMILES indeed learns the spatial relationships between atoms within a molecule. These results provide encouraging evidence that large-scale molecular language models can capture sufficient chemical and structural information to predict various distinct molecular properties, including quantum-chemical properties.

Large Language Models (LLMs) have demonstrated remarkable proficiency in understanding and generating natural language. However, their capabilities wane in highly specialized domains underrepresented in the pretraining corpus, such as physical and biomedical sciences. This work explores how to repurpose general LLMs into effective task solvers for specialized domains. We introduce a novel, model-agnostic framework for learning custom input tags, which are parameterized as continuous vectors appended to the LLM's embedding layer, to condition the LLM. We design two types of input tags: domain tags are used to delimit specialized representations (e.g., chemical formulas) and provide domain-relevant context; function tags are used to represent specific functions (e.g., predicting molecular properties) and compress function-solving instructions. We develop a three-stage protocol to learn these tags using auxiliary data and domain knowledge. By explicitly disentangling task domains from task functions, our method enables zero-shot generalization to unseen problems through diverse combinations of the input tags. It also boosts LLM's performance in various specialized domains, such as predicting protein or chemical properties and modeling drug-target interactions, outperforming expert models tailored to these tasks.

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language Models (pLMs) aim to unlock insights from the vast space of unlabeled protein sequences by learning rich, semantic representations from primary sequences via masked language modeling. However, these models typically exhibit limited generative capacity. In this work, we introduce the Diffusion Sequence Model (DSM), a novel pLM trained with masked diffusion to enable both high-quality representation learning and generative protein design. DSM builds upon the ESM2 architecture by incorporating a masked forward diffusion process inspired by the LLaDA framework. After training, DSM is capable of generating diverse, biomimetic sequences that align with expected amino acid compositions, secondary structures, and predicted functions, even with 90\% token corruption. Furthermore, DSM's learned representations match or exceed those of similarly sized pLMs on downstream tasks. We also introduce DSM(ppi), a variant fine-tuned to generate protein binders by attending to target sequences. We demonstrate DSM(ppi)'s effectiveness on the challenging Bench-tested Binder Benchmark (BenchBB), where both DSM and DSM(ppi) produce candidates with superior predicted binding affinity compared to known binders. Our results establish masked diffusion as a powerful paradigm for unifying protein representation and generation in a single framework.

Molecular generative models, often employing GPT-style language modeling on molecular string representations, have shown promising capabilities when scaled to large datasets and model sizes. However, it remains unclear and subject to debate whether these models adhere to predictable scaling laws under fixed computational budgets, which is a crucial understanding for optimally allocating resources between model size, data volume, and molecular representation. In this study, we systematically investigate the scaling behavior of molecular language models across both pretraining and downstream tasks. We train 300 models and conduct over 10,000 experiments, rigorously controlling compute budgets while independently varying model size, number of training tokens, and molecular representation. Our results demonstrate clear scaling laws in molecular models for both pretraining and downstream transfer, reveal the substantial impact of molecular representation on performance, and explain previously observed inconsistencies in scaling behavior for molecular generation. Additionally, we publicly release the largest library of molecular language models to date to facilitate future research and development. Code and models are available at https://github.com/SZU-ADDG/MLM-Scaling.

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

General-purpose large language models (LLMs) that rely on in-context learning do not reliably deliver the scientific understanding and performance required for drug discovery tasks. Simply increasing model size or introducing reasoning tokens does not yield significant performance gains. To address this gap, we introduce the MMAI Gym for Science, a one-stop shop molecular data formats and modalities as well as task-specific reasoning, training, and benchmarking recipes designed to teach foundation models the 'language of molecules' in order to solve practical drug discovery problems. We use MMAI Gym to train an efficient Liquid Foundation Model (LFM) for these applications, demonstrating that smaller, purpose-trained foundation models can outperform substantially larger general-purpose or specialist models on molecular benchmarks. Across essential drug discovery tasks - including molecular optimization, ADMET property prediction, retrosynthesis, drug-target activity prediction, and functional group reasoning - the resulting model achieves near specialist-level performance and, in the majority of settings, surpasses larger models, while remaining more efficient and broadly applicable in the domain.

Molecule pretraining has quickly become the go-to schema to boost the performance of AI-based drug discovery. Naturally, molecules can be represented as 2D topological graphs or 3D geometric point clouds. Although most existing pertaining methods focus on merely the single modality, recent research has shown that maximizing the mutual information (MI) between such two modalities enhances the molecule representation ability. Meanwhile, existing molecule multi-modal pretraining approaches approximate MI based on the representation space encoded from the topology and geometry, thus resulting in the loss of critical structural information of molecules. To address this issue, we propose MoleculeSDE. MoleculeSDE leverages group symmetric (e.g., SE(3)-equivariant and reflection-antisymmetric) stochastic differential equation models to generate the 3D geometries from 2D topologies, and vice versa, directly in the input space. It not only obtains tighter MI bound but also enables prosperous downstream tasks than the previous work. By comparing with 17 pretraining baselines, we empirically verify that MoleculeSDE can learn an expressive representation with state-of-the-art performance on 26 out of 32 downstream tasks.

Based on the BioBricks standard, restriction synthesis is a novel catabolic iterative DNA synthesis method that utilizes endonucleases to synthesize a query sequence from a reference sequence. In this work, the reference sequence is built from shorter subsequences by classifying them as applicable or inapplicable for the synthesis method using three different machine learning methods: Support Vector Machines (SVMs), random forest, and Convolution Neural Networks (CNNs). Before applying these methods to the data, a series of feature selection, curation, and reduction steps are applied to create an accurate and representative feature space. Following these preprocessing steps, three different pipelines are proposed to classify subsequences based on their nucleotide sequence and other relevant features corresponding to the restriction sites of over 200 endonucleases. The sensitivity using SVMs, random forest, and CNNs are 94.9%, 92.7%, 91.4%, respectively. Moreover, each method scores lower in specificity with SVMs, random forest, and CNNs resulting in 77.4%, 85.7%, and 82.4%, respectively. In addition to analyzing these results, the misclassifications in SVMs and CNNs are investigated. Across these two models, different features with a derived nucleotide specificity visually contribute more to classification compared to other features. This observation is an important factor when considering new nucleotide sensitivity features for future studies.

Current protein language models (PLMs) learn protein representations mainly based on their sequences, thereby well capturing co-evolutionary information, but they are unable to explicitly acquire protein functions, which is the end goal of protein representation learning. Fortunately, for many proteins, their textual property descriptions are available, where their various functions are also described. Motivated by this fact, we first build the ProtDescribe dataset to augment protein sequences with text descriptions of their functions and other important properties. Based on this dataset, we propose the ProtST framework to enhance Protein Sequence pre-training and understanding by biomedical Texts. During pre-training, we design three types of tasks, i.e., unimodal mask prediction, multimodal representation alignment and multimodal mask prediction, to enhance a PLM with protein property information with different granularities and, at the same time, preserve the PLM's original representation power. On downstream tasks, ProtST enables both supervised learning and zero-shot prediction. We verify the superiority of ProtST-induced PLMs over previous ones on diverse representation learning benchmarks. Under the zero-shot setting, we show the effectiveness of ProtST on zero-shot protein classification, and ProtST also enables functional protein retrieval from a large-scale database without any function annotation.

Interrogating the evolution of biological changes at early stages of life requires longitudinal profiling of molecules, such as DNA methylation, which can be challenging with children. We introduce a probabilistic and longitudinal machine learning framework based on multi-mean Gaussian processes (GPs), accounting for individual and gene correlations across time. This method provides future predictions of DNA methylation status at different individual ages while accounting for uncertainty. Our model is trained on a birth cohort of children with methylation profiled at ages 0-4, and we demonstrated that the status of methylation sites for each child can be accurately predicted at ages 5-7. We show that methylation profiles predicted by multi-mean GPs can be used to estimate other phenotypes, such as epigenetic age, and enable comparison to other health measures of interest. This approach encourages epigenetic studies to move towards longitudinal design for investigating epigenetic changes during development, ageing and disease progression.

Accurate prediction of atomistic, thermodynamic, and kinetic properties from molecular structures underpins materials innovation. Existing computational and experimental approaches lack the scalability required to efficiently navigate chemical space. Scientific foundation models trained on large unlabeled datasets offer a path toward exploring chemical space across diverse application domains. Here we develop MIST, a family of molecular foundation models with up to an order of magnitude more parameters and data than prior works. Trained using a novel tokenization scheme that comprehensively captures nuclear, electronic, and geometric information, MIST learns from a diverse range of molecules. MIST models have been fine-tuned to predict more than 400 structure -- property relationships and match or exceed state-of-the-art performance across benchmarks spanning physiology, electrochemistry, and quantum chemistry. We demonstrate the ability of these models to solve real-world problems across chemical space, including multiobjective electrolyte solvent screening, olfactory perception mapping, isotope half-life prediction, stereochemical reasoning for chiral organometallic compounds, and binary and multi-component mixture property prediction. Probing MIST models using mechanistic interpretability methods reveals identifiable patterns and trends not explicitly present in the training data, suggesting that the models learn generalizable scientific concepts. We formulate hyperparameter-penalized Bayesian neural scaling laws and use them to reduce the computational cost of model development by an order of magnitude. The methods and findings presented here represent a significant step toward accelerating materials discovery, design, and optimization using foundation models and provide valuable guidance for training compute-optimal scientific foundation models.

Large language models (LLMs) have gained significant attention in chemistry. However, most existing datasets center on molecular-level property prediction and overlook the role of fine-grained functional group (FG) information. Incorporating FG-level data can provide valuable prior knowledge that links molecular structures with textual descriptions, which can be used to build more interpretable, structure-aware LLMs for reasoning on molecule-related tasks. Moreover, LLMs can learn from such fine-grained information to uncover hidden relationships between specific functional groups and molecular properties, thereby advancing molecular design and drug discovery. Here, we introduce FGBench, a dataset comprising 625K molecular property reasoning problems with functional group information. Functional groups are precisely annotated and localized within the molecule, which ensures the dataset's interoperability thereby facilitating further multimodal applications. FGBench includes both regression and classification tasks on 245 different functional groups across three categories for molecular property reasoning: (1) single functional group impacts, (2) multiple functional group interactions, and (3) direct molecular comparisons. In the benchmark of state-of-the-art LLMs on 7K curated data, the results indicate that current LLMs struggle with FG-level property reasoning, highlighting the need to enhance reasoning capabilities in LLMs for chemistry tasks. We anticipate that the methodology employed in FGBench to construct datasets with functional group-level information will serve as a foundational framework for generating new question-answer pairs, enabling LLMs to better understand fine-grained molecular structure-property relationships. The dataset and evaluation code are available at https://github.com/xuanliugit/FGBench.

The approval success rate of drug candidates is very low with the majority of failure due to safety and efficacy. Increasingly available high dimensional information on targets, drug molecules and indications provides an opportunity for ML methods to integrate multiple data modalities and better predict clinically promising drug targets. Notably, drug targets with human genetics evidence are shown to have better odds to succeed. However, a recent tensor factorization-based approach found that additional information on targets and indications might not necessarily improve the predictive accuracy. Here we revisit this approach by integrating different types of human genetics evidence collated from publicly available sources to support each target-indication pair. We use Bayesian tensor factorization to show that models incorporating all available human genetics evidence (rare disease, gene burden, common disease) modestly improves the clinical outcome prediction over models using single line of genetics evidence. We provide additional insight into the relative predictive power of different types of human genetics evidence for predicting the success of clinical outcomes.

The overwhelming majority of molecules remains unexplored. This is mostly due to the sheer number of them, which prohibits any enumeration of chemical space, the set of all such molecules. In practice, only subsets of chemical space are considered, but those subsets exhibit substantial bias, prohibiting data-driven characterization of chemical space itself. In this work, we provide a method produce unbiased representative random samples of chemical space without enumeration of constituent molecules and to estimate the number of molecules in any custom chemical space. The approach is applicable to molecules which can be represented as graph and runs efficiently even for molecules of 30 atoms. We use it to estimate the representativeness of current databases with respect to their underlying chemical space and to establish a necessary criterion for a lower bound of database sizes to be representative of an underlying chemical space.

Genomic alterations lead to cancer complexity and form a major hurdle for a comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe the recent advances in studying cancer-associated genes from a systems biological point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in the information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, the genes, which are involved in the regulation of cancer progression, can be picked up from these networks after which their functions can be further confirmed in the laboratory.

Two-dimensional (2D) Nuclear Magnetic Resonance (NMR) spectroscopy, particularly Heteronuclear Single Quantum Coherence (HSQC) spectroscopy, plays a critical role in elucidating molecular structures, interactions, and electronic properties. However, accurately interpreting 2D NMR data remains labor-intensive and error-prone, requiring highly trained domain experts, especially for complex molecules. Machine Learning (ML) holds significant potential in 2D NMR analysis by learning molecular representations and recognizing complex patterns from data. However, progress has been limited by the lack of large-scale and high-quality annotated datasets. In this work, we introduce 2DNMRGym, the first annotated experimental dataset designed for ML-based molecular representation learning in 2D NMR. It includes over 22,000 HSQC spectra, along with the corresponding molecular graphs and SMILES strings. Uniquely, 2DNMRGym adopts a surrogate supervision setup: models are trained using algorithm-generated annotations derived from a previously validated method and evaluated on a held-out set of human-annotated gold-standard labels. This enables rigorous assessment of a model's ability to generalize from imperfect supervision to expert-level interpretation. We provide benchmark results using a series of 2D and 3D GNN and GNN transformer models, establishing a strong foundation for future work. 2DNMRGym supports scalable model training and introduces a chemically meaningful benchmark for evaluating atom-level molecular representations in NMR-guided structural tasks. Our data and code is open-source and available on Huggingface and Github.

Organic Solar Cells are a promising technology for solving the clean energy crisis in the world. However, generating candidate chemical compounds for solar cells is a time-consuming process requiring thousands of hours of laboratory analysis. For a solar cell, the most important property is the power conversion efficiency which is dependent on the highest occupied molecular orbitals (HOMO) values of the donor molecules. Recently, machine learning techniques have proved to be very useful in building predictive models for HOMO values of donor structures of Organic Photovoltaic Cells (OPVs). Since experimental datasets are limited in size, current machine learning models are trained on data derived from calculations based on density functional theory (DFT). Molecular line notations such as SMILES or InChI are popular input representations for describing the molecular structure of donor molecules. The two types of line representations encode different information, such as SMILES defines the bond types while InChi defines protonation. In this work, we present an ensemble deep neural network architecture, called SINet, which harnesses both the SMILES and InChI molecular representations to predict HOMO values and leverage the potential of transfer learning from a sizeable DFT-computed dataset- Harvard CEP to build more robust predictive models for relatively smaller HOPV datasets. Harvard CEP dataset contains molecular structures and properties for 2.3 million candidate donor structures for OPV while HOPV contains DFT-computed and experimental values of 350 and 243 molecules respectively. Our results demonstrate significant performance improvement from the use of transfer learning and leveraging both molecular representations.

Generative Flow Networks (GFlowNets) have recently emerged as a suitable framework for generating diverse and high-quality molecular structures by learning from rewards treated as unnormalized distributions. Previous works in this framework often restrict exploration by using predefined molecular fragments as building blocks, limiting the chemical space that can be accessed. In this work, we introduce Atomic GFlowNets (A-GFNs), a foundational generative model leveraging individual atoms as building blocks to explore drug-like chemical space more comprehensively. We propose an unsupervised pre-training approach using drug-like molecule datasets, which teaches A-GFNs about inexpensive yet informative molecular descriptors such as drug-likeliness, topological polar surface area, and synthetic accessibility scores. These properties serve as proxy rewards, guiding A-GFNs towards regions of chemical space that exhibit desirable pharmacological properties. We further implement a goal-conditioned finetuning process, which adapts A-GFNs to optimize for specific target properties. In this work, we pretrain A-GFN on a subset of ZINC dataset, and by employing robust evaluation metrics we show the effectiveness of our approach when compared to other relevant baseline methods for a wide range of drug design tasks. The code is accessible at https://github.com/diamondspark/AGFN.

Developing therapeutics is a lengthy and expensive process that requires the satisfaction of many different criteria, and AI models capable of expediting the process would be invaluable. However, the majority of current AI approaches address only a narrowly defined set of tasks, often circumscribed within a particular domain. To bridge this gap, we introduce Tx-LLM, a generalist large language model (LLM) fine-tuned from PaLM-2 which encodes knowledge about diverse therapeutic modalities. Tx-LLM is trained using a collection of 709 datasets that target 66 tasks spanning various stages of the drug discovery pipeline. Using a single set of weights, Tx-LLM simultaneously processes a wide variety of chemical or biological entities(small molecules, proteins, nucleic acids, cell lines, diseases) interleaved with free-text, allowing it to predict a broad range of associated properties, achieving competitive with state-of-the-art (SOTA) performance on 43 out of 66 tasks and exceeding SOTA on 22. Among these, Tx-LLM is particularly powerful and exceeds best-in-class performance on average for tasks combining molecular SMILES representations with text such as cell line names or disease names, likely due to context learned during pretraining. We observe evidence of positive transfer between tasks with diverse drug types (e.g.,tasks involving small molecules and tasks involving proteins), and we study the impact of model size, domain finetuning, and prompting strategies on performance. We believe Tx-LLM represents an important step towards LLMs encoding biochemical knowledge and could have a future role as an end-to-end tool across the drug discovery development pipeline.

Human medical data can be challenging to obtain due to data privacy concerns, difficulties conducting certain types of experiments, or prohibitive associated costs. In many settings, data from animal models or in-vitro cell lines are available to help augment our understanding of human data. However, this data is known for having low etiological validity in comparison to human data. In this work, we augment small human medical datasets with in-vitro data and animal models. We use Invariant Risk Minimisation (IRM) to elucidate invariant features by considering cross-organism data as belonging to different data-generating environments. Our models identify genes of relevance to human cancer development. We observe a degree of consistency between varying the amounts of human and mouse data used, however, further work is required to obtain conclusive insights. As a secondary contribution, we enhance existing open source datasets and provide two uniformly processed, cross-organism, homologue gene-matched datasets to the community.

The detection of ligand binding sites for proteins is a fundamental step in Structure-Based Drug Design. Despite notable advances in recent years, existing methods, datasets, and evaluation metrics are confronted with several key challenges: (1) current datasets and methods are centered on individual protein-ligand complexes and neglect that diverse binding sites may exist across multiple complexes of the same protein, introducing significant statistical bias; (2) ligand binding site detection is typically modeled as a discontinuous workflow, employing binary segmentation and subsequent clustering algorithms; (3) traditional evaluation metrics do not adequately reflect the actual performance of different binding site prediction methods. To address these issues, we first introduce UniSite-DS, the first UniProt (Unique Protein)-centric ligand binding site dataset, which contains 4.81 times more multi-site data and 2.08 times more overall data compared to the previously most widely used datasets. We then propose UniSite, the first end-to-end ligand binding site detection framework supervised by set prediction loss with bijective matching. In addition, we introduce Average Precision based on Intersection over Union (IoU) as a more accurate evaluation metric for ligand binding site prediction. Extensive experiments on UniSite-DS and several representative benchmark datasets demonstrate that IoU-based Average Precision provides a more accurate reflection of prediction quality, and that UniSite outperforms current state-of-the-art methods in ligand binding site detection. The dataset and codes will be made publicly available at https://github.com/quanlin-wu/unisite.

Traditional drug design faces significant challenges due to inherent chemical and biological complexities, often resulting in high failure rates in clinical trials. Deep learning advancements, particularly generative models, offer potential solutions to these challenges. One promising algorithm is DrugGPT, a transformer-based model, that generates small molecules for input protein sequences. Although promising, it generates both chemically valid and invalid structures and does not incorporate the features of approved drugs, resulting in time-consuming and inefficient drug discovery. To address these issues, we introduce DrugGen, an enhanced model based on the DrugGPT structure. DrugGen is fine-tuned on approved drug-target interactions and optimized with proximal policy optimization. By giving reward feedback from protein-ligand binding affinity prediction using pre-trained transformers (PLAPT) and a customized invalid structure assessor, DrugGen significantly improves performance. Evaluation across multiple targets demonstrated that DrugGen achieves 100% valid structure generation compared to 95.5% with DrugGPT and produced molecules with higher predicted binding affinities (7.22 [6.30-8.07]) compared to DrugGPT (5.81 [4.97-6.63]) while maintaining diversity and novelty. Docking simulations further validate its ability to generate molecules targeting binding sites effectively. For example, in the case of fatty acid-binding protein 5 (FABP5), DrugGen generated molecules with superior docking scores (FABP5/11, -9.537 and FABP5/5, -8.399) compared to the reference molecule (Palmitic acid, -6.177). Beyond lead compound generation, DrugGen also shows potential for drug repositioning and creating novel pharmacophores for existing targets. By producing high-quality small molecules, DrugGen provides a high-performance medium for advancing pharmaceutical research and drug discovery.

The integration of molecule and language has garnered increasing attention in molecular science. Recent advancements in Language Models (LMs) have demonstrated potential for the comprehensive modeling of molecule and language. However, existing works exhibit notable limitations. Most existing works overlook the modeling of 3D information, which is crucial for understanding molecular structures and also functions. While some attempts have been made to leverage external structure encoding modules to inject the 3D molecular information into LMs, there exist obvious difficulties that hinder the integration of molecular structure and language text, such as modality alignment and separate tuning. To bridge this gap, we propose 3D-MolT5, a unified framework designed to model both 1D molecular sequence and 3D molecular structure. The key innovation lies in our methodology for mapping fine-grained 3D substructure representations (based on 3D molecular fingerprints) to a specialized 3D token vocabulary for 3D-MolT5. This 3D structure token vocabulary enables the seamless combination of 1D sequence and 3D structure representations in a tokenized format, allowing 3D-MolT5 to encode molecular sequence (SELFIES), molecular structure, and text sequences within a unified architecture. Alongside, we further introduce 1D and 3D joint pre-training to enhance the model's comprehension of these diverse modalities in a joint representation space and better generalize to various tasks for our foundation model. Through instruction tuning on multiple downstream datasets, our proposed 3D-MolT5 shows superior performance than existing methods in molecular property prediction, molecule captioning, and text-based molecule generation tasks. Our code will be available on GitHub soon.

Advancements in DNA sequencing technologies have significantly improved our ability to decode genomic sequences. However, the prediction and interpretation of these sequences remain challenging due to the intricate nature of genetic material. Large language models (LLMs) have introduced new opportunities for biological sequence analysis. Recent developments in genomic language models have underscored the potential of LLMs in deciphering DNA sequences. Nonetheless, existing models often face limitations in robustness and application scope, primarily due to constraints in model structure and training data scale. To address these limitations, we present GENERator, a generative genomic foundation model featuring a context length of 98k base pairs (bp) and 1.2B parameters. Trained on an expansive dataset comprising 386B bp of eukaryotic DNA, the GENERator demonstrates state-of-the-art performance across both established and newly proposed benchmarks. The model adheres to the central dogma of molecular biology, accurately generating protein-coding sequences that translate into proteins structurally analogous to known families. It also shows significant promise in sequence optimization, particularly through the prompt-responsive generation of promoter sequences with specific activity profiles. These capabilities position the GENERator as a pivotal tool for genomic research and biotechnological advancement, enhancing our ability to interpret and predict complex biological systems and enabling precise genomic interventions.