KRAS G12C as a Target of Naringenin for Inducing Cell Death in NCI-H23 Cells

Background: Naringenin (NGN) is a commonly available flavonoid in the citrus fruits. We have previously shown that NGN is cytotoxic to the non-small cell lung cancer (NSCLC) cell line NCI-H23 (H23). Objectives: To check whether NGN could bind to the Kirsten rat sarcoma (KRAS) G12C mutant and cause its inhibition to promote apoptosis in H23 cells. Materials and Methods: NGN was docked with mutant KRAS protein followed by molecular dynamics simulation. HDOCK was used to analyse the influence of NGN on the KRAS and PI3K proteinprotein docking. We checked the ultramorphological structure of the cells. A 2D-QSAR study was carried out to predict the activity of NGN. Results: We observed that NGN bound stably to the mutant KRAS. NGN showed steady RMSF and RMSD values, good structural stability, and favourable MM/PBSA values. NGN interfered in the binding of KRAS and PI3K. NGN treated cells showed hallmarks of apoptotic cell death. The predictive pIC₅₀ value was found to be 7.39 for NGN against KRAS. NGN cleared all the drug filters. Conclusion: We conclude that NGN could bind to the mutant KRAS potentially inhibiting KRAS. That affects the PI3K/Akt pathway activation leading to apoptosis in the NCI-H23 cells.