We next investigated the impact of these two KRAS(G12C) inhibitors on the SII-P conserved water, which is associated to Thr58 (Figure ). This conserved water exist in numerous SII-P binder co-crystal structures and is of an interest for KRAS targeted drug discovery . Our simulations suggest that GDC-6036 promotes partially the displacement of the water from this location (Figure ). The region appears without any water molecules slightly above half of the simulation time (50.9%). GDC-6036 does not contain any polar atoms in the proximity of the conserved water location, which would either promote the full replacement of the water by occupying its location and replacing interactions with Gly10 and Thr58 or introduce an attractive interaction with the conserved water (Figures and). Quite the reverse is observed with LY3537982, which introduces an ether oxygen next to the conserved water location that can participate to water-mediated interactions (Figures and). This is also reflected in the water occupation, as with LY3537982 a water molecule is observed 80.1% of the time in the conserved water location (Figure ). Next, we analyzed the impact of these inhibitors on Thr58. In the simulations of GDC-6036, Thr58