Lipinski's Rule of Five — BBB Permeability Heuristic
Lipinski's Rule of Five (Lipinski 1997, 2001) is the foundational medicinal-chemistry rule for predicting whether a small molecule will cross the blood-brain barrier (BBB) by passive diffusion.
The four criteria
A molecule is likely BBB-permeable if it satisfies all four:
- Molecular weight (MW) <= 500 Daltons
- Octanol-water partition coefficient (logP) <= 5
- Hydrogen-bond donors <= 5
- Hydrogen-bond acceptors <= 10
Molecules violating two or more criteria are typically poorly absorbed or impermeant.
Why ethanol crosses
Ethanol (CCO) has MW=46 Da, logP=-0.31, 1 H-bond donor, 1 H-bond acceptor — well within all four thresholds. This explains its rapid CNS penetration despite hydrophilicity.
SHAP attribution interpretation
When a Random Forest BBB classifier flags Morgan fingerprint bits with positive SHAP values toward a "permeable" label, the bit usually corresponds to a small lipophilic substructure (CH3-, -OCH3-, aromatic ring) consistent with Lipinski compliance.