Therefore, here we set out to analyze the nature of this conserved water in more detail with the published SII-P binders. We applied the WaterMap methodology and microsecond timescale molecular dynamics (MD) simulations with two different water models (TIP3P and TIP4P) to enlighten the potential role of this water in KRAS targeted drug discovery. Our results reveal the high-energy nature of this conserved water in the presence of SII-P binders and its suboptimal replacement with the few compounds that displace this water to date. These findings offer important insights into the conserved water and will aid the ongoing and future ligand/drug design efforts towards the most promising druggable KRAS pocket to date.