Explicit Ligand hydration shells improve the correlation between MM-PB/GBSA binding energies and experimental activities

Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) methods are widely used for drug design/discovery purposes. However, it is not clear if the correlation between predicted and experimental binding affinities can be improved by explicitly considering selected water molecules in the calculation of binding energies, since different and sometimes diverging opinions are found in the literature. In this work, we evaluated how variably populated hydration shells explicitly considered around the ligands may affect the correlation between MM-PB/GBSA computed binding energy and biological activities (IC50 and ΔGbind, depending on the available experimental data). Four different systems—namely, the DNA-topoisomerase complex, α-thrombin, penicillopepsin, and avidin—were considered and ligand hydration shells populated by 10–70 water molecules were systematically evaluated. We found that the consideration of a hydration shell populated by a number of water residues (Nwat) between 30 and 70 provided, in all of the considered examples, a positive effect on correlation between MM-PB/GBSA calculated binding affinities and experimental activities, with a negligible increment of computational cost.