Including tightly-bound water molecules in de novo drug design. Exemplification through the in silico generation of poly(ADP-ribose)polymerase ligands

Different strategies for the in silico generation of ligand molecules in the binding site of poly(ADP-ribose)polymerase (PARP) were studied in order to observe the effect of the targeting and displacement of tightly bound water molecules. Several molecular scaffolds were identified as having better interactions in the binding site when targeting one or two tightly bound water molecules in the NAD binding site. Energy calculations were conducted in order to assess the ligand-protein and ligand-water-protein interactions of different functional groups of the generated ligands. These calculations were used to evaluate the energetic consequences of the presence of tightly bound water molecules and to identify those that contribute favorably to the binding of ligands.