Mechanistic Insights into Passive Membrane Permeability of Drug-like Molecules from a Weighted Ensemble of Trajectories

Passive permeability
of a drug-like molecule is a critical property
assayed early in a drug discovery campaign that informs a medicinal
chemist how well a compound can traverse biological membranes, such
as gastrointestinal epithelial or restrictive organ barriers, so it
can perform a specific therapeutic function. However, the challenge
that remains is the development of a method, experimental or computational,
which can both determine the permeation rate and provide mechanistic
insights into the transport process to help with the rational design
of any given molecule. Typically, one of the following three methods
are used to measure the membrane permeability: (1) experimental permeation
assays acting on either artificial or natural membranes; (2) quantitative
structure–permeability relationship models that rely on experimental
values of permeability or related pharmacokinetic properties of a
range of molecules to infer those for new molecules; and (3) estimation
of permeability from the Smoluchowski equation, where free energy
and diffusion profiles along the membrane normal are taken as input
from large-scale molecular dynamics simulations. While all these methods
provide estimates of permeation coefficients, they provide very little
information for guiding rational drug design. In this study, we employ
a highly parallelizable weighted ensemble (WE) path sampling strategy,
empowered by cloud computing techniques, to generate unbiased permeation
pathways and permeability coefficients for a set of drug-like molecules
across a neat 1-palmitoyl-2-oleoyl-sn-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.