Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.
Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRASG12C complex highlighted an unprecedented binding mode.
['Mortier|Jérémie|J|0000-0001-8707-3867', 'Friberg|Anders|A|', 'Badock|Volker|V|', 'Moosmayer|Dieter|D|', 'Schroeder|Jens|J|', 'Steigemann|Patrick|P|', 'Siegel|Franziska|F|', 'Gradl|Stefan|S|', 'Bauser|Marcus|M|', 'Hillig|Roman C|RC|', 'Briem|Hans|H|', 'Eis|Knut|K|', 'Bader|Benjamin|B|', 'Nguyen|Duy|D|', 'Christ|Clara D|CD|']
D000494:Allosteric Regulation D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D006801:Humans D015394:Molecular Structure D009154:Mutation D016283:Proto-Oncogene Proteins p21(ras) D013329:Structure-Activity Relationship
KRAS molecular dynamics free-energy perturbation (FEP) medicinal chemistry virtual library design