To Pass or Not To Pass: Predicting the Blood–Brain Barrier Permeability with the 3D-RISM-KH Molecular Solvation Theory

Predicting the ability of chemical species to cross the blood-brain barrier (BBB) is an active field of research for development and mechanistic understanding in the pharmaceutical industry. Here, we report the BBB permeability of a large data set of compounds by incorporating molecular solvation energy descriptors computed by the 3D-RISM-KH molecular solvation theory. We have been able to show, for the first time, that the computed excess chemical potential in different solvents can be successfully used to predict permeability of compounds in a binary manner (yes/no) via a minimum-descriptor-based model. Our findings successfully combine the molecular solvation theory with the machine learning approach to address one of the most daunting challenges in predictive structure-activity relationship modeling. The workflow presented in this work is simple enough to be used by nonexperts with ease.