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Updated: Jun 4, 2025
Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
Published on: January 16, 2020
Structure-based interaction study of Samaderine E and Bismurrayaquinone A phytochemicals as potential inhibitors of
Z Hasan1, M Y Areeshi2, R K Mandal2
1Department of Biosciences, Jamia Millia Islamia (Central University), New Delhi, India.
Abstract:
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.
Insights
Researchers screened phytochemicals to find KRas inhibitors for cancer therapy. Samaderine E and Bismurrayaquinone A show potential as therapeutic agents by binding to KRas and altering its function.
Area of Science:
- Oncology
- Computational Chemistry
- Pharmacology
Background:
- Ras proteins are crucial oncogenes frequently mutated in human cancers.
- KRas, a specific isoform, is the most commonly mutated, leading to uncontrolled cell signaling and growth.
- Inhibiting KRas is a key strategy for cancer treatment.
Purpose of the Study:
- To identify novel phytochemical inhibitors of the KRas oncoprotein.
- To analyze the binding interactions and mechanisms of potential KRas inhibitors.
- To evaluate the therapeutic potential of identified phytochemicals.
Main Methods:
- Structure-based virtual screening of 11,698 phytochemicals from the IMPPAT 2.0 database.
- Detailed analysis of binding patterns and molecular dynamics (MD) simulations (200 ns) for identified compounds.
- Computational analyses including RMSD, RMSF, Rg, SASA, hydrogen bond analysis, secondary structure analysis, PCA, and FEL analysis.
Main Results:
- Two phytochemicals, Samaderine E and Bismurrayaquinone A, were identified with significant binding affinity to KRas.
- These compounds bind to key residues (ARG41 and ASP54) within the KRas binding site, inducing conformational changes.
- MD simulations and subsequent analyses confirmed the stability and interaction mechanisms of the phytochemical-KRas complexes.
Conclusions:
- Samaderine E and Bismurrayaquinone A demonstrate potential as effective therapeutic inhibitors of the KRas oncoprotein.
- The identified phytochemicals bind to a functional pocket on KRas, offering a promising avenue for cancer drug development.
- Further research into these compounds could lead to novel KRas-targeted cancer therapies.
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