We next investigated the water behavior on the Thr58 associated conserved water site in the presence of the SII-P binding inhibitors in more detail, using microsecond timescale molecular dynamics (MD) simulations . Here we focused our analysis on six selected systems (three G12C, two G12D and one G12S systems). We selected from the KRAS(G12C) SII-P binders the clinically approved sotorasib (PDB ID: 6OIM) , Novartis compound JDQ443 (PDB ID: 7R0M) , and Astra-Zeneca compound AZD4625 (PDB ID: 7O70) . All these KRAS(G12C)inhibitor complexes contain the conserved water in their crystal structures, while WaterMap simulations predicted high-energy or even dewetted cavity (for JDQ443) on this hydration site (Table , Figure , Figure ). We chose the MRTX1133 (PDB ID: 7RPZ) and another lower affinity compound of the Mirati-series "compound 5B" (PDB ID: 7RT4) , which contained adjacent waters in the crystal structure and in the WaterMap hydration site analysis, from the G12D structures (Table , Figure , Figure ). Finally, we selected the covalent inhibitor G12Si-1 (PDB ID: 7TLE) designed by Shokat et al. from the G12S structures; for this structure, WaterMap suggested clearly lower (but still high) energy for the water compared to other systems (Table , Figure ).