The reason for the improved performance observed for the diverse datasets in this study is presumably due to the capture of interactions between the ligand and the closest of the four conserved water molecules also found in the binding site. This observation is in line with other work in which system dependent numbers of water molecules were found to improve rankings and the broader phenomenon of the impact of crucial water molecules on SAR landscapes. Incorporation of the water molecules was highly effective in differentiating the ligands with diverse binding modes but less effective in the set of related THQ-scaffold based compounds. The fact that our observations fit a general pattern, and that the level of explicit water hydration that improves results is similar to the number of conserved water molecules suggests that the general approach can be applied more generally.