Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

摘要

Assessment of permeability is a critical step in the drug development process for selection of drug candidates with favorable ADME properties. We have developed a novel physics-based method for fast computational modeling of passive permeation of diverse classes of molecules across lipid membranes. The method is based on heterogeneous solubility−diffusion theory and operates with all-atom 3D structures of solutes and the anisotropic solvent model of the lipid bilayer characterized by transbilayer profiles of dielectric and hydrogen bonding capacity parameters. The optimal translocation pathway of a solute is determined by moving an ensemble of representative conformations of the molecule through the dioleoyl-phosphatidylcholine (DOPC) bilayer and optimizing their rotational orientations in every point of the transmembrane trajectory. The method calculates (1) the membrane-bound state of the solute molecule; (2) free energy profile of the solute along the permeation pathway; and (3) the permeability coefficient obtained by integration over the transbilayer energy profile and assuming a constant size-dependent diffusivity along the membrane normal. The accuracy of the predictions was evaluated against experimental permeability coefficients measured in pure lipid membranes (for 78 compounds, R² was 0.88 and rmse was 1.15 log units), PAMPA-DS (for 280 compounds, R² was 0.75 and rmse was 1.59 log units), BBB (for 182 compounds, R² was 0.69 and rmse was 0.87 log units), and Caco-2/MDCK assays (for 165 compounds, R² was 0.52 and rmse was 0.89 log units).