Bioinformatics and computational exploration of novel inhibitors targeting KRAS G12C mutant protein in lung adenocarcinoma.

BACKGROUND: The KRAS p.G12C mutation is a major oncogenic driver in lung adenocarcinoma (LUAD), a prevalent subtype of non-small cell lung cancer (NSCLC). The development of sotorasib has provided a new targeted therapeutic option for patients with this mutation. METHODS: KRAS G12C mutations and expression in LUAD were analyzed. A pharmacophore model-based screening of over 1.4 billion conformations was conducted. Molecular docking, drug-likeness, pharmacokinetics, and toxicity predictions were carried out to explore ligands. Binding stability and key residue interactions were evaluated using extra-precision docking, molecular dynamics, H-bond lifetimes, FEL, PCA, and MM-GBSA analyses. RESULTS: , hydrogen bond dynamics, FEL and PCA revealed distinct dynamic behaviors among ligands. Key ligands, including PubChem-137,082,465, PubChem-137,304,698, PubChem-137,304,606, and PubChem-154,677,904, demonstrated favorable predicted binding interactions and dynamic stability, with in silico profiles broadly comparable to that of sotorasib. MM-GBSA and per-residue decomposition indicated ARG68, TYR96, and GLN99 as conserved interaction residues critical for ligand stabilization. CONCLUSIONS: The compounds, including PubChem-137,082,465 and PubChem-154,677,904, exhibited favorable binding and favorable interaction profiles, comparable to sotorasib, positioning them as computationally prioritized candidates for KRAS p.G12C inhibition in LUAD.