Recently, Shokat's group reported the first covalent inhibitors of KRAS(G12S) with a b-lactone warhead reacting to the mutant serine residue (PDB IDs: 7TLE; 7TLG). Interestingly, these inhibitors present a hydroxyl-group towards the conserved water after the covalent reaction have taken place (Figure ). Among all SII-P binders with an isolated hydration site, WaterMap predicts the lowest energy for these G12S inhibitors (only surmounted by ARS-853 (Table )) (Table ). The lower energy of this water is explained by the low enthalpy due to the H-bond interaction to the ligand, where the hydroxyl acts as an acceptor (G12Si-1: DH = +0.36, -TDS = +5.05 kcal/mol; G12Si-5 chain B: DH = +1.26, -TDS = +4.53 kcal/mol; G12Si-5 chain A: DH = +4.24, -TDS = +3.18 kcal/mol). Here we noted a discrepancy in WaterMap predicted energies on the conserved water site between the chains A and B of G12Si-5 (PDB ID: 7TLG) (Figure ). This discrepancy is explained by the slightly shifted orientation of the Lys16 towards the conserved water, which alters the environment (Figure ).