The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models

The importance of the consideration of water molecules in the structural interpretation of ligand-derived pharmacophore models is explored. We compare and combine results from recently introduced methods for bound-water molecule identification in protein binding sites and ligand-superposition-based pharmacophore derivation, for the interpretation of ligand-derived pharmacophore models. In the analysis of thymidine kinase (HSV-1) and poly (ADP-ribose) polymerase (PARP), the concurrent application of both methods leads to an agreement in the prediction of tightly bound water molecules as key pharmacophoric points in the binding site of these proteins. This agreement has implications for approaching binding site analysis and consensus drug design, as it highlights how pharmacophore-based models of binding sites can include interaction features not only with protein groups but also with bound water molecules.