The discovery of some promising putative binders of KRAS G12D receptor using computer-aided drug discovery approach

Abstract

A prospective target for the therapy of solid tumors is KRAS G12D, the most prevalent oncogenic KRAS mutation. However, despite decades of research that focused on the identification of druggable compounds against this highly challenging therapeutic cancer target, no drug has been clinically approved for the treatment of KRAS G12D-driven cancers. Herein, we employed computational techniques such as molecular docking and molecular dynamics simulations to investigate small-molecule compounds with the potential to bind putatively with KRAS G12D. The docking screening portrayed three compounds (Quercetin, Psoralidin, and Resveratrol) as promising drug candidates for the receptor target due to their higher binding affinities when compared with a known noncovalent, potent, and selective KRAS G12D inhibitor (MRTX1133). The stability analysis after 100000 ps molecular dynamics simulation suggests Quercetin as a more stable compound when compared with the other simulated chemical entities, including the referenced inhibitor (MRTX1133). In spite of our research findings, it will be too early to conclude the drug candidates can be advanced to the clinic for use with KRAS G12D cancer patients without extensive preclinical and clinical studies.

Keywords

• Cancer therapeutics
• Computer-aided drug design
• KRAS G12D
• Molecular docking
• Molecular dynamics simulation