G12Si-1 and "compound 5B" the least. Obviously, this discrepancy may also be partially mediated via the inhibitor-switch-II interactions, as switch-II fluctuations and conformation are interlinked to the water access to this conserved site. Interestingly, a dramatic instability of the ligand near the conserved water site was observed in one of the simulation replicas of "compound 5B". This compound was also the only one from the simulated set for which WaterMap predicted an adjacent hydration site next to the conserved water site. Related to the used water models on the conserved water site, TIP4P water model exhibited closer contacts to the protein and more stable interactions, while TIP3P was more dynamic and reflected better to the WaterMap results.