Predictions of Skin Permeability Using Molecular Dynamics Simulation from Two-Dimensional Sampling of Spatial and Alchemical Perturbation Reaction Coordinates

A molecular level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics, skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skins barrier structure and predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates with so-called Accelerated Weight Histograms, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for twenty permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the ob-tained [Formula] mean square difference was 0.8 cm2 h-2.