Volume 20, Issue 46, July - December, 2026

Ensemble docking and molecular dynamics validation of quinazoline c9 targeting mutant kras(g12c)

Stephen Adebayo Osasan^1,7♦, George Oche Ambrose², Olusola Daramola³, Oluwafemi Ayodele Adefolalu⁴, Alzahrani A. Hind⁵, Mohammad Alshehri Jawaher⁶, Wisdom Onuche Ibrahim², Olanrewaju I Ajetunmobi⁸

¹Department of Laboratory Medicine, Ministry of Health (Prince Mishari Bin Saud Hospital, Baljurashi, Al-Baha), Kingdom of Saudi Arabia
²University of Ilorin Teaching Hospital, Ilorin, Nigeria
³North Devon District Hospital, Barnstaple, United Kingdom
⁴Obafemi Awolowo University Teaching Hospital, Ile-Ife, Osun State, Nigeria
⁵Department of Basic Science, College of Applied Medical Sciences, University of Al-Baha, Al-Baha, Saudi Arabia
⁶Optometry Department, Faculty of Applied Medical Sciences, Al- Baha University, Al-Baha, Saudi Arabia
⁷Saudi Arabia Board of Preventive Medicine, Al-Baha, Saudi Arabia
⁸Department of Histopathology, University Hospitals Morecambe Bay, NHS Trust, Kendal, United Kingdom

^♦Corresponding Author
Osasan Stephen Adebayo, Department of Laboratory Medicine, Ministry of Health, Prince Mishari Bin Saud Hospital, Baljurashi, Al-Baha, Saudi Arabia

ABSTRACT

The KRAS(G12C) mutations represent a major oncogenic driver in multiple types of cancer. Covalent inhibitors such as sotorasib have shown clinical efficacy, but identifying alternative scaffolds that can stabilise the Switch-II pocket remains an important goal in targeted drug discovery. In this study, combined docking analyses of two crystal structures, 7O70 and 7O83, were performed, and it was observed that C9 has better binding affinity (-7.0 and -8.0 kcal/mol) than sotorasib (-5.4 and -6.6 kcal/mol) and can attain good ligand recognition in different conformations. The interaction network analysis showed that C9 interacts with key residues in the Switch-II pocket, such as CYS12, GLU62, ARG68, ASP69, ASP92, MET72, HIS95 and TYR96, via complementary electrostatic, aromatic and hydrophobic interactions. Importantly, the mutant residue CYS12 and aromatic stacking with TYR96 could stabilise the ligand in a stable state by π-sulfur contacts. Molecular dynamics simulations (100 ns) showed the complexes to be stable. The RMSD trajectories suggested stable protein backbones and ligand poses, with the C9 complexes showing lower ligand RMSD values than the control in the 7O70 system. Furthermore, the radius of gyration analysis suggested that KRAS remained globally compact during the simulations. Energetic decomposition of ligand-protein interaction energies showed that van der Waals interactions were the main contributors to the binding stabilisation. Consistently negative interaction energies were observed for the C9 complexes, especially in the 7O70 system. Taken together, these results indicate that the quinazoline compound C9 makes stable contacts in the KRAS(G12C) binding pocket, and may be a favourable scaffold for the development of next-generation KRAS(G12C) inhibitors.

Keywords: KRAS(G12C), Quinazoline C9, Molecular docking, Molecular dynamics simulation, Switch-II pocket, Targeted cancer therapy

Drug Discovery, 2026, 20(45), e17dd3099

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Published: 18 August 2026