When "compound 5B" is compared to MRTX1133, it is lacking the Asp69 interactions and displays clearly diminished direct interaction to Gly60 of switch-II (88-91% and 15-23%, respectively) (Figures ). These missing interactions offer a putative explanation of "compound 5B" instability, and experimentally observed lower binding affinity compared to MRTX1133 (Table ). The only compound engaging actively in interactions with the conserved water is G12Si-1. It maintains the water-bridged interaction to Gly10 from its hydroxyl group with 33-40% frequency in the simulations (Figures ). G12Si-1 interactions to Lys16, which is in the proximity of the conserved water site, are clearly lower (19-36%) compared to what is observed for other covalent inhibitors (43-95%) (Figures ).