Passive membrane permeation of small molecules is essential to achieve the required absorption, distribution, metabolism and excretion profiles of drug candidates and is also central to transport across the blood-brain-barrier. Computational investigations of this process typically involve performing potential of mean force free energy calculations of the permeation event in order to derive permeability coefficients by application of the inhomogeneous solubility-diffusion model.<br/><br/>In this work, we instead combine free energy of transfer results for membrane permeation with unbiased simulations of membrane partitioning and flip-flop, capturing the important steps of permeation and allowing calculation of the kinetic rates between each step. Kinetic results are then applied in a dynamic mechanistic model of <i>in vitro</i> liposomal permeation, which includes the transient changes in compound concentration within the membrane as species partition and then translocate. This allows a systems-level investigation of membrane transport and the derivation of structure-kinetic relationships of permeation for a collection of drug-like compounds.

Structure-kinetic relationships of passive membrane permeation from multiscale modeling

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.