Mechanistic Insights into Passive Membrane Permeability of Drug-like Molecules from a Weighted Ensemble of Trajectories
She Zhang, Jeffrey P. Thompson, Junchao Xia, Anthony T. Bogetti, Forrest York, A. Geoffrey Skillman, Lillian T. Chong, David N. LeBard
Abstract
-glycero-3-phosphatidylcholine membrane bilayer. Our WE method predicts permeability coefficients that compare well to experimental values from an MDCK-LE cell line and PAMPA assays for a set of drug-like amines of varying size, shape, and flexibility. Our method also yields a series of continuous permeation pathways weighted and ranked by their associated probabilities. Taken together, the ensemble of reactive permeation pathways, along with the estimate of the permeability coefficient, provides a clearer picture of the microscopic underpinnings of small-molecule membrane permeation.
Topics & Concepts
PermeationMembranePermeability (electromagnetism)ChemistryMolecular dynamicsLipid bilayerDrug discoveryMembrane permeabilityBiological systemPotential of mean forceComputational chemistryBiochemistryBiologyLipid Membrane Structure and BehaviorDNA and Nucleic Acid ChemistryDrug Transport and Resistance Mechanisms