Prediction of Solvation Free Energies of Small Organic Molecules: Additive-Constitutive Models Based on Molecular Fingerprints and Atomic Constants

Abstract

Solvation free energy is an important molecular characteristic useful in drug discovery because it represents the desolvation cost of a ligand binding to a receptor. Most of the recent developments in the estimation of solvation free energy require the use of molecular mechanics and dynamics calculations. Group contribution methods have been rarely used in the past for calculating solvation free energy because automated prediction methods have not been developed in this regard. As an aid to combinatorial library design, we explored rapid and accurate means of computing solvation free energies from the covalent structures of organic molecules and compared the results on a test set with the GB/SA solvation model. Two independent additive-constitutive QSPR methods have been developed for the computation of solvation free energy. The first is a QSPR model (HLOGS) derived using a technique that uses the counts of distinct/similar fragments and substructures for each molecule as variables in a PLS regression. T...