New Developments in Hydrogen Bonding Acidity and Basicity of Small Organic Molecules for the Prediction of Physical and ADMET Properties. Part 2. The Universal Solvation Equation

Theoretical quantifications of hydrogen bonding (HB) basicities and acidities, originally developed for aliphatic systems (J. Chem. Inf. Comput. Sci. 2004, 44, 1042−1055), are now extended to cover aromatic, heterocyclic, anionic, cationic and zwitter-ionic molecular fragments, thus encompassing a majority of druggable chemical space. The addition of terms accounting for cavity formation, polarity, hydrophobicity, and resonance allowed us to derive a new equation able to predict accurately free energies of solvation of diverse solutes, interphase transfers, and aqueous solubilities (log Sw). We thus provide a “universal solvation equation” (USE) available for the accurate estimation of desolvation energies in protein−ligand docking, for the prediction of many physical and ADMET properties, and for studying fluid phase equilibria.