Shokat's group also reported the first covalent inhibitors of KRAS(G12R) with α,β-diketoamides as reacting warheads towards the mutated arginine residue . The one publicly available co-crystal structure reveals that the conserved water is displaced by the cyanomethyl group of "compound 4" (Figure -B; Table ). Interestingly, WaterMap suggests that a high-energy hydration site appears adjacent to this site with the chain A of 8CX5 on the switch-II side (+10.23 kcal/mol). Notably, this is not observed with the G12C-inhibitors with the cyanomethyl (PDB IDs: 6USZ; 6UT0) (Figure ; Figure ). This is likely due to different conformations of Arg68 and Thr58, which in a different configuration with the G12R-inhibitor "compound 4" vacate a suitable space for a water molecule in that location with chain A (Figure ). However, with chain B no waters are observed in the conserved site or adjacent to it. Interestingly, a similar altered conformation of Thr58 (where the hydroxyl is flipped away from the ligand and Gly10), which was observed with cyanomethyl containing G12C binders adagrasib and "compound 12a" (6USZ; 6UT0) (Figure , Figure ), is preferred only in chain B of G12R