Roberto Menichetti and Tristan Bereau, Molecular Physics (2019)

Using high-throughput drug-membrane free-energy calculations to explore the Meyer-Overton rule

Assessing the permeation rate of drug-like molecules across a lipid membrane is of paramount importance for pharmaceutical applications. While the Meyer-Overton rule relates the permeability coefficient to a few thermodynamic properties, its accuracy is limited by the homogeneity assumption. In this work, we extract an analogous relation for the permeation of a small solute through a lipid bilayer. This is obtained by systematically screening a subset of chemical space by means of high-throughput coarse-grained simulations, and relying on the accurate inhomogeneous solubility-diffusion model (ISDM). We connect the permeability coefficient of a compound to two molecular descriptors: partitioning free-energy and acid dissociation constant. In the ISDM the permeability is a functional of the potential of mean force. We discuss how – and when – combining together these profiles for a large variety of compounds can result in a smooth dependence of the permeability on the molecular descriptors. We focus on acidic molecules: for weak acids, the permeability largely depends on the main free-energy differences of the problem, which directly link to our molecular descriptors. For strong acids, the multivalued nature of the permeability requires to introduce a third variable, characterising the amphiphilicity of the small molecule.