Here, however, our WaterMap analysis failed to demonstrate this as a beneficial effect, as a lower energy of the conserved water was not associated with MRTX1133. When compared to the other inhibitors of the Mirati G12D-series, we observed that the flagship compound MRTX1133 and "compound 36", which both contain 8-ethynyl, employ this moiety to displace the adjacent hydration sites (adjacent waters also present in the crystal structures) next to the conserved water that are present with the other inhibitors of the series (Figure , Figure ). This kind of adjacent hydration sites are also observed for instance with the low affinity (K D > 1,500 µM) fragment GNE-2897, which is co-crystallized in the presence of the switch-II stabilizing antibody (PDB ID: 7MDP) , as well as with some of the first generation G12C inhibitors with lower activity (PDB IDs: 4LV6; 4LUC) (Table , Figure , Figure , Figure ). In contrast to the covalent inhibitors binding exclusively to inactive GDP-bound KRAS(G12C), MRTX1133 is also capable to bind active GTP-bound KRAS(G12D) (PDB ID: 7T47) . The Thr58 associated conserved water appears in the MRTX1133 structures regardless of the bound nucleotide (PDB IDs: 7RPZ (GDP); 7T47 (GTP-analogue GCP)). WaterMap predicts a comparable energy value for the conserved water of these structures (+9.24 and +9.54 kcal/mol) (Figure ), suggesting a negligible effect of the g-phosphate (of GTP) on this hydration site.