A new explicit hydration penalty score for ligand–protein interactions

A novel method for estimating hydration penalties in ligand–protein interactions is introduced. This method is based on a series of separate Monte Carlo simulations in explicit water of the ligand, the protein and the ligand–protein complex. The average net gain or loss of hydrogen bonds in the solvent upon ligand–protein binding is computed to provide a hydration penalty score. This method is tested on a few CDK-2 inhibitors and is able to discriminate between inhibitors where other approximate methods fail.