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

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.

Dietary polyphenols mitigate SARS-CoV-2 main protease (Mpro)-Molecular dynamics, molecular mechanics, and density functional theory investigations.

The recent evolution of the SARS-like Coronavirus has ravaged the world. The deadly virus has claimed over millions of lives across the world and hence highlights the need to develop effective therapeutic drugs to contain the disease posed by this parasite. In this study, the inhibitory potential of fifty (50) dietary polyphenols against Coronavirus (SARS-CoV-2) main protease (Mpro) was conducted using the Autodock Vina Molecular docking tool. In the virtual screening process, the binding affinity of Remdesivir (-7.7 kcal/mol) currently used to treat COVID-19 patients was set as the cut-off value to screen out less probable inhibitors. Ellagic acid, Kievitone, and Punicalin were the only promising ligands with binding affinities (-8.9 kcal/mol, -8.0 kcal/mol and -7.9 kcal/mol respectively) lower than the set cut-off value. Furthermore, we validated Ellagic acid and Kievitone efficacy by subjecting them to molecular dynamics simulation and further stability was assessed at the molecular mechanics and quantum levels. The overall analysis indicates both compounds demonstrate higher stability and inhibitory potential to bind to the crucial His41 and Cys145 catalytic dyad of Mpro than the standard drug. However, further analysis of punicalin after evaluating its docking score was not conducted as the ligand pharmacokinetics properties suggests it could pose serious adverse effect to the health of participants in clinical trials. Hence, we employed a more safe approach by filtering out the compound during this study. Conclusively, while Ellagic acid and kievitone polyphenolic compounds have been demonstrated to be promising under this in silico research, further studies are needed to substantiate their clinical relevance.