Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses

Abstract

KRAS mutations linked with cancer. Flavonoids were docked against KRAS G12C and G12D receptors. Abyssinone III, alpha naphthoflavone, beta naphthoflavone, abyssinone I, abyssinone II and beta naphthoflavone, genistin, daidzin showed good docking scores against KRAS G12C and G12D receptors, respectively. The MD simulation data revealed that Rg, RMSD, RMSF, and SASA values were within acceptable limits. Alpha and beta naphthoflavone showed good binding energies with KRAS G12C and G12D receptors. DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

HIGHLIGHTS

• In the present study, we computationally established the role of flavonoids as KRAS G12C and G12D inhibitors.

• Initially we selected 93 flavonoids and docked against 8AFB (KRAS G12C) and 7RT1 (KRAS G12D) using Sotorasib and MRTX 1133 as standards.

• A 100 ns MD simulation revealed that the radius of gyration, RMSD, RMSF, and SASA values were within acceptable limits and that there were a greater number of donors and acceptors for hydrogen bonds.

• In addition to the KRAS G12C 8AFB receptor, the maximum binding energy was shown by alpha Naphthoflavone (−26.471 kJ/mol), and for the KRAS G12D 7RT1 receptor, the maximum binding energy was shown by beta Naphthoflavone (−15.433 kJ/mol).

• FMO and MEP analysis data highlighted the best-docked flavonoids’ potential areas for nucleophilic and electrophilic attacks.

• ADMET properties have been calculated and provide safe use and low toxicity for both aquatic and non-aquatic species.

Keywords:

• flavonoids
• KRAS
• molecular docking
• MD simulation
• ADMET

Acknowledgements

Authors conveyed special thanks to Mr. JitenderJoshi, Chancellor, and Prof. (Dr.) Dharam Buddhi, Vice Chancellor of Uttaranchal University Dehradun encourages publishing this research work. We are grateful to the Division of Research and Innovation (DRI) and Central Instrumentation Facility (CIF), Uttaranchal University-Dehradun, India for providing all facilities during the experimental work, and Research Cell and Publications, University of Chittagong, Bangladesh for financial and technical support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financially supported by the Uttaranchal University to S Saha and Research and Publications Cell, University of Chittagong, Bangladesh to SMA Kawsar.