Our predicted binding modes suggest a different behavior related to the conserved water with these two inhibitors in the clinical trials. Only a handful of SII-P binders displacing or interacting with this conserved water have been reported to date . While GDC-6036 appears repulsive to the conserved water and is partially capable in displacing it, LY3537982 approaches the binding differently by introducing water mediated H-bond interactions through this water and supports its existence on the location. Still, by introducing these water-bridged interactions to Gly10, LY3537982 appears to distort the native conformation of Thr58. Based on our biochemical data LY3537982 is more potent than GDC-6036, but also its behavior is untypical in the used assays.