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Pharmacophoric analogs of sotorasib-entrapped KRAS G12C in its inactive GDP-bound conformation: covalent docking and molecular dynamics investigations.
Pharmacophoric analogs of sotorasib-entrapped KRAS G12C in its inactive GDP-bound conformation: covalent docking and molecular dynamics investigations.
- Source :
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Molecular diversity [Mol Divers] 2023 Aug; Vol. 27 (4), pp. 1795-1807. Date of Electronic Publication: 2022 Oct 21. - Publication Year :
- 2023
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Abstract
- 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&#95;146235944, CID&#95;160070181, and CID&#95;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.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Details
- Language :
- English
- ISSN :
- 1573-501X
- Volume :
- 27
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular diversity
- Publication Type :
- Academic Journal
- Accession number :
- 36271195
- Full Text :
- https://doi.org/10.1007/s11030-022-10534-1