Pharmacophoric analogs of sotorasib-entrapped KRAS G12C in its inactive GDP-bound conformation: covalent docking and molecular dynamics investigations.

Autor: Oyedele AK; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria.; Department of Chemistry, University of New Haven, West Haven, CT, USA.; Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria., Ogunlana AT; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria., Boyenle ID; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria.; Department of Chemistry and Biochemistry, University of Maryland, Maryland, USA.; College of Health Sciences, Crescent University, Abeokuta, Nigeria., Ibrahim NO; Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria., Gbadebo IO; Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria., Owolabi NA; Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria., Ayoola AM; Biochemistry Unit, Department of Chemical Sciences, College of Natural and Applied Science, Fountain University, Osogbo, Nigeria., Francis AC; Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria., Eyinade OH; Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria., Adelusi TI; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria. tiadelusi@lautech.edu.
Jazyk: angličtina
Zdroj: Molecular diversity [Mol Divers] 2023 Aug; Vol. 27 (4), pp. 1795-1807. Date of Electronic Publication: 2022 Oct 21.
DOI: 10.1007/s11030-022-10534-1
Abstrakt: For decades, KRAS G12C was considered an undruggable target. However, in recent times, a covalent inhibitor known as sotorasib was discovered and approved for the treatment of patients with KRAS G12C-driven cancers. Ever since the discovery of this drug, several preclinical efforts have focused on identifying novel therapeutic candidates that could act as covalent binders of KRAS G12C. Despite these intensive efforts, only a few KRAS G12C inhibitors have entered clinical trials. Hence, this highlights the need to develop effective drug candidates that could be used in the treatment of KRAS G12C-driven cancers. Herein, we embarked on a virtual screening campaign that involves the identification of pharmacophores of sotorasib that could act as covalent arsenals against the KRAS G12C target. To our knowledge, this is the first computational study that involves the compilation of sotorasib pharmacophores from an online chemical database against KRAS G12C. After this library of chemical entities was compiled, we conducted a covalent docking-based virtual screening that revealed three promising drug candidates (CID_146235944, CID_160070181, and CID_140956845) binding covalently to the crucial nucleophilic side chain of Cys12 and interact with the residues that form the cryptic allosteric pocket of KRAS G12C in its inactive GDP-bound conformation. Subsequently, ADMET profiling portrayed the covalent inhibitors as lead-like candidates, while 100 ns molecular dynamics was used to substantiate their stability. Although our overall computational study has shown the promising potential of the lead-like candidates in impeding oncogenic RAS signaling, more experimental efforts are needed to validate and establish their preclinical relevance. Implication of KRAS G12C in cancer and computational approach towards impeding the KRAS G12C RAS signaling.
(© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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