Covalent docking-based virtual screening and molecular dynamics simulations identify C02b as a potential KRAS(G12C) inhibitor

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 compounds analogous to Sotorasib, resulting in the discovery of a total of 174 Sotorasib scaffold-compounds. We then performed covalent docking-based virtual screening to examine the binding affinity of Sotorasib-like compounds to KRAS(G12C). Four compounds showed comparable binding energies according to Glide score to Sotorasib for targeting KRAS(G12C). Subsequently, molecular dynamics (MD) simulations were conducted for these four compounds, spanning 100 ns, 300 ns, and 500 ns durations, to identify the most stable complex with the lowest root-mean-square deviation (RMSD), similar to the KRAS(G12C)-Sotorasib reference complex. Additional dynamic cross-correlation matrix and PCA were performed as post-MD analyses to investigate the movements of two switches and the flexible 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 investigations beyond this study may provide more insight into C02b’s inhibitory effect on KRAS(G12C), offering a deeper understanding of its potential as a therapeutic agent.