Characterization of the binding of MRTX1133 as an avenue for the discovery of potential KRASG12D inhibitors for cancer therapy.

The Kirsten rat sarcoma (KRAS) oncoprotein has been on drug hunters list for decades now. Initially considered undruggable, recent advances have successfully broken the jinx through covalent inhibition that exploits the mutated cys12 in the switch II binding pocket (KRASG12C). Though this approach has achieved some level of success, patients with mutations other than cys12 are still uncatered for. KRASG12D is the most frequent KRAS mutated oncoprotein. It is only until recently, MRTX1133 has been discovered as a potential inhibitor of KRASG12D. This study seeks to unravel the structural binding mechanism of MRTX1133 as well as identify potential drug leads of KRASG12D based on structural binding characteristics of MRTX1133. It was revealed that MRTX1133 binding stabilizes the binding site by increasing the hydrophobicity which resultantly induced positive correlated movements of switches I and II which could disrupt their interaction with effector and regulatory proteins. Furthermore, MRTX1133 interacted with critical residues; Asp69 (- 4.54 kcal/mol), His95 (- 3.65 kcal/mol), Met72 (- 2.27 kcal/mol), Thr58 (- 2.23 kcal/mol), Gln99 (- 2.03 kcal/mol), Arg68 (- 1.67 kcal/mol), Tyr96 (- 1.59 kcal/mol), Tyr64 (- 1.34 kcal/mol), Gly60 (- 1.25 kcal/mol), Asp12 (- 1.04 kcal/mol), and Val9 (- 1.03 kcal/mol) that contributed significantly to the total free binding energy of - 73.23 kcal/mol. Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRASG12D inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRASG12D inhibitors.