Predicting Blood–Brain Partitioning of Small Molecules Using a Novel Minimalistic Descriptor-Based Approach via the 3D-RISM-KH Molecular Solvation Theory

Compartmentalization of drug molecules between plasma and brain is important for desired activities. The difficulty in obtaining the blood–brain permeability of drug (like) substances experimentally resulted in the development of several theoretical quantitative structure–activity relationships toward predicting the capability of a given substrate to pass across a tight junction, known as the blood–brain barrier, both qualitatively and quantitatively. Here, we report a novel method based on the molecular solvation theory for predicting blood–brain barrier permeability coefficients of molecules of diverse structures using a minimum set of descriptors derived from solvation energetics. Our finding points to the importance of solvation free energy based descriptors in modeling blood–brain barrier permeability quantitatively.