Bioinfo Chem

Targeting Mutant KRAS G12C with Berberine Derivatives: A Molecular Docking and Dynamics Approach in Colorectal Cancer

Shahadat Hossain1*, Md. Taufique Hasan Bhuiyan Sezan2, Moin Uddin Patwary3

Berberine offers a natural, safe, and multi-pathway alternative for selectively targeting KRAS G12C in colorectal cancer therapy development.

Abstract

Background: A lot of people die of colorectal cancer in general. One major fact about the issue is the mutated KRAS G12C mutation that causes the cells to multiply out of hand because it keeps some of the signaling lines active at all times. Sotorasib is a new drug which is effective in selected patients but it resists and causes side-effects, not to mention that need lower-toxicity drugs that strike multiple targets. That is why researching into Berberine, which is a natural alkaloid and have anticancer effects.

Methods: Established molecular docking simulations in Auto Dock Vina to identify the location of Berberine and Sotorasib binding with mutant KRAS G12C. The leading binding is fed with the 100-nanosecond molecular dynamics setups with the AMBER force field, and the spectacles considered include RMSD, RMSF, and hydrogen bonds. Another experiment that performed involved SILAC based proteomics having provided the cells with Berberine to determine which proteins would be on or off. Gene Ontology enrichment assisted me to determine the pathways that were struck - particularly in terms of kinase activity, enzyme regulation as well as primary oncogenic signals.

Results: The docking indicated that Berberine binds to KRAS G12C with a -8.6 kcal/mol binding energy, slightly less than Sotorasib. Molecular dynamics informed me that the complex remains stable, RMSD is small and little change in shape. SILAC data indicates that Berberine can push KRAS-related pathways in the right direction, without disrupting the whole proteome. GO analysis has identified such aspects as calmodulin binding, kinase activity, and control of apoptosis.

Conclusion: In general, it is possible to state that Berberine and its analogues appear to be safer and more effective as compared to the currently used KRAS G12C inhibitors due to their ability to act on multiple cancer-relevant pathways.

Keywords: KRAS G12C, Colorectal Cancer, Berberine, Sotorasib, Molecular Docking

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