Using Membrane Partitioning Simulations To Predict Permeability of Forty-Nine Drug-Like Molecules

A simple descriptor calculated from molecular dynamics simulations of the membrane partitioning event is found to correlate well with experimental measurements of passive membrane permeation from the high-throughput MDCK-LE assay using a data set of 49 drug-like molecules. This descriptor approximates the energy cost of translocation across the hydrophobic membrane core (flip-flop), which for many molecules limits permeability. Performance is found to be superior in comparison to calculated properties such as clogP, clogD, or polar surface area. Furthermore, the atomistic simulations provide a structural understanding of the partitioned drug–membrane complex, facilitating medicinal chemistry optimization of membrane permeability.