Structure-based interaction study of Samaderine E and Bismurrayaquinone A phytochemicals as potential inhibitors of KRas oncoprotein.

Ras is identified as a human oncogene which is frequently mutated in human cancers. Among its three isoforms (K, N, and H), KRas is the most frequently mutated. Mutant Ras exhibits reduced GTPase activity, leading to the prolonged activation of its conformation. This extended activation promotes Ras-dependent signalling, contributing to cancer cell survival and growth. In this study, we conducted structure-based virtual screening of 11698 phytochemicals in the IMPPAT 2.0 database to identify inhibitors of KRas. We identified two phytochemicals with fair binding affinity, and their binding patterns with KRas were analysed in detail. Additionally, we performed 200 ns molecular dynamics (MD) simulations of each complex to understand the interaction mechanism of KRas with the newly identified compounds, such as Samaderine E and Bismurrayaquinone A. These phytochemicals bind to the binding site residues ARG41 and ASP54, causing conformational changes in KRas. The RMSD, RMSF, Rg, SASA, hydrogen bond, and secondary structure analysis studies suggested the potential of the selected phytochemicals. The identification of Samaderine E and Bismurrayaquinone A as phytochemicals binding to a functional pocket on KRas, supported by PCA and FEL analysis, highlights their potential as effective therapeutic inhibitors of the KRas oncoprotein.