Page 87 - TD-4-1

Tumor Discovery

ORIGINAL RESEARCH ARTICLE
Covalent docking-based virtual screening and

molecular dynamics simulations identify C02b as
a potential KRAS(G12C) inhibitor

2
1
Safiye Merve Bostancioglu * and Ahmet Acar *
1 Department of Biology, Faculty of Arts and Sciences, Marmara University, Goztepe Campus,
Istanbul, Turkey
2 Department of Biological Sciences, Middle East Technical University, Universiteler Mah., Ankara,
Turkey

Abstract

Decades of efforts to target the “undruggable” Kirsten rat sarcoma viral oncogene
homolog (KRAS) oncoprotein yielded promising results in 2021 with the approval of
Sotorasib, a KRAS(G12C) inhibitor for non-small cell lung cancer patients with the
KRAS(G12C) variant. Before Sotorasib’s approval, developing KRAS(G12C) covalent
inhibitors faced challenges, particularly their inability to preserve the KRAS protein
in the GDP-bound state, which hindered clinical trial progression. Considering the
importance of developing inhibitors targeting KRAS(G12C), we aimed to identify
*Corresponding authors: compounds analogous to Sotorasib, resulting in the discovery of a total of 174
Safiye Merve Bostancioglu Sotorasib scaffold-compounds. We then performed covalent docking-based
(mervebostancioglu@marun.edu.tr);
Ahmet Acar virtual screening to examine the binding affinity of Sotorasib-like compounds to
(acara@metu.edu.tr) KRAS(G12C). Four compounds showed comparable binding energies according to
Citation: Acar A, Bostancioglu SM. Glide score to Sotorasib for targeting KRAS(G12C). Subsequently, molecular dynamics
Covalent docking-based virtual (MD) simulations were conducted for these four compounds, spanning 100 ns,
screening and molecular dynamics 300 ns, and 500 ns durations, to identify the most stable complex with the lowest
simulations identify C02b as a
potential KRAS(G12C) inhibitor. root-mean-square deviation (RMSD), similar to the KRAS(G12C)-Sotorasib reference
Tumor Discov. 2025;4(1):79-98. complex. Additional dynamic cross-correlation matrix and PCA were performed as
doi: 10.36922/td.5163 post-MD analyses to investigate the movements of two switches and the flexible
Received: October 15, 2024 regions of KRAS(G12C)-Sotorasib and -C02b complexes. As a result, among these
four compounds, KRAS(G12C)-C02b was found as the optimal candidate. Further
Revised: November 30, 2024
investigations beyond this study may provide more insight into C02b’s inhibitory
Accepted: December 9, 2024 effect on KRAS(G12C), offering a deeper understanding of its potential as a therapeutic
Published online: December 26, agent.
2024
Copyright: © 2024 Author(s). Keywords: KRAS(G12C); Sotorasib-like compounds; Molecular dynamics simulations
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium, 1. Introduction
provided the original work is
properly cited. Cancer is a complex disease characterized by the number of key hallmarks, including
Publisher’s Note: AccScience sustained proliferative signaling, evasion of growth suppressors, resistance to cell
Publishing remains neutral with death, enabling replicative immortality, inducing angiogenesis, activation of invasion
regard to jurisdictional claims in
published maps and institutional and metastasis, deregulation of cellular energetics, avoidance of immune destruction,
affiliations. promotion of inflammation, genome instability and mutation, and alteration of

Volume 4 Issue 1 (2025) 79 doi: 10.36922/td.5163