All three G12D SII-P binder structures reported by Mao et al. exist with an isolated conserved high-energy hydration site (Table ). Here, the ligand with highest activity display (slightly) lower or similar energy (+8.29 kcal/mol) compared to the less active compounds of the series (+8.73 and +9.71 kcal/mol) (Table , Figure ). Interestingly, the co-crystal structure containing TH-Z827 has no water assigned in this site in the crystal structure (PDB ID: 7EWA) , but the Fo-Fc difference map displays positive density at this location (Figure ), potentially indicating the presence of water in the site, which is also supported by the WaterMap (Table , Figure ).