Computational Screening of Marchantia polymorpha Against KRAS G12C Mutation in Non-Small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) constitutes approximately 85% of all lung cancer cases and is a leading cause of cancer-related mortality worldwide. Despite advances in cancer therapies, many current treatments are associated with severe side effects, complicating therapeutic protocols and adversely impacting patients’ quality of life. Recent in-silico studies have highlighted the potential of plant-derived phytochemicals as alternative therapeutic agents targeting genetic mutations implicated in cancer progression. In a prior study, we demonstrated the anticancer properties of Marchantia polymorpha L. extract on A549 cells. This study aims to discover small molecules that may act as inhibitors on KRAS G12C mutant protein from Marchantia polymorpha metabolites using in silico methods. The affinity value of Marchantia polymorpha L. secondary metabolites for the KRAS G12C mutated protein was determined by molecular docking analysis. Metabolites with high-affinity values and interacting with cysteine at position 12 were selected. Pharmacokinetic and toxicity studies of the selected metabolites were performed. All results were compared with the drug adagrasib and a plant-based small molecule that could be an inhibitor of the KRAS G12C mutation was discovered. Our computational analyses identified Rosmarinic Acid and Chlorogenic Acid, two natural compounds, as promising inhibitors of the KRAS G12C mutation. These compounds exhibited inhibitory efficacy comparable to Adagrasib, a clinically approved KRAS G12C inhibitor. Rosmarinic Acid and Chlorogenic Acid, with their favorable safety profiles and potential to inhibit KRAS G12C, represent promising natural and cost-effective alternatives for NSCLC treatment. Further experimental validation and clinical studies are warranted to explore their therapeutic potential.