Discovery of Novel c-MET Inhibitors for Hepatocellular Carcinoma Using an Integrated Virtual Screening Approach

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with the efficacy of current targeted therapies limited by drug resistance and adverse effects. The receptor tyrosine kinase c-MET has been identified as a promising target for HCC therapy due to its involvement in tumor progression, metastasis, and poor prognosis. However, no c-MET inhibitors have been approved for HCC treatment. This study integrates a multistep virtual screening workflow, incorporating molecular docking, machine learning-based predictions, and molecular dynamics simulations, to identify novel c-MET inhibitors with unique structural frameworks. Among several promising candidates, compound 10 exhibited potent c-MET inhibition and selective antiproliferative effects against the HCC cell line Hep3B. Further molecular dynamics simulations confirmed the binding stability of compound 10 with c-MET, highlighting key interactions that contribute to its inhibitory activity. These findings provide valuable insights into the development of c-MET inhibitors with potential therapeutic applications for HCC.