Discovery of a Potent c-MET Inhibitor for Non-Small Cell Lung Cancer Treatment by AI-Based and Docking-Based Virtual Screening

The dysregulation of the mesenchymal-epithelial transition factor (c-MET) signaling pathway is linked to the development and drug resistance of non-small cell lung cancer (NSCLC), highlighting the need for small-molecule inhibitors targeting c-MET. In this study, we identified six potential c-MET inhibitors from a compound library using structure-based and AI-based virtual screening. Four compounds demonstrated c-MET inhibitory activity, with compound <b>2</b> exhibiting potent inhibition at an IC₅₀ of 40.1 nM. Further studies showed that compound <b>2</b> effectively inhibited NSCLC cell proliferation, comparable to that of positive controls. ADMET predictions indicate favorable drug-like properties, suggesting its potential as a novel c-MET inhibitor. Molecular dynamics simulations revealed that compound <b>2</b> stabilizes its conformation through interactions with Ala1221, Pro1158, and Lys1110, providing valuable insights for further drug development.