A total of eight structures have been published where the Thr58 associated conserved water is displaced (Figure , Table ). Kettle et al. were the first ones to publicly disclose a co-crystal structure of a SII-P binder, "compound 25", displacing the conserved water (PDB ID: 6T5B) (Figure ; Figure ). The introduction of a chiral (R-)methyl-group to displace the conserved water, in turn promoted the compound's bioactive conformation, significantly boosting the potency. Interestingly, in the 6T5B structure a positive (electron) density in the location of the conserved water is observed based on the Fo-Fc difference map (Figure ), leaving a possibility for the water existence in this location. Still, WaterMap does not predict a hydration site in this location (Figure ). Bayer scientists introduced compounds with carbonyl group of isoquinolinone replacing the water and forming a H-bond to Gly10 (PDB IDs: 6TAM; 6TAN) (Figure , Figure ; Figure ). Mirati scientists applied a cyanoethyl strategy in their series to displace the conserved water, and to interact with Gly10 (PDB IDs: 6UT0; 6USZ) (Figure , Figure , Figure ). Introducing the cyanoethyl boosted the potency 300-fold and this cyanoethyl is present in adagrasib for which FDA approval is expected in late 2022. Novartis "compound 2" (PDB ID: 7R0N) displaces the conserved water by introducing its phenyl-ring on the site (Figure , Figure ). Finally, a distal methyl in a heterocyclic ring system occupies the conserved water site with AstraZeneca's "compound 23" (PDB ID: 7O83) and Amgen's WO2020/178282A1 (PDB ID: 8DNJ) (Figure , Figure ). However, a similar scaffold in this location is not a guarantee for the conserved water displacement (PDB IDs: 7OO7; 7O70) (Table , Figure ). The native conformation of Thr58 is altered with all the four compounds that are reaching deeper into the pocket, and engaging Gly10 with an electronegative atom (fully shifted in 6UT0, 6USZ ; ambiguous in 6TAM, 6TAN) (Figure ). Analogous conformation distortion of Thr58 is not observed with the non-polar displacers that are not reaching as deep into the pocket (6T5B 42 ; 7R0N 46 ; 7O83 47 ; 8DNJ 49 ) (Figure , Figure ).