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

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Dysregulation of the mesenchymal-epithelial transition factor (c-MET) signaling pathway is implicated in non-small cell lung cancer (NSCLC) development and drug resistance.
• Targeting c-MET with small-molecule inhibitors is a crucial strategy for NSCLC treatment.

Purpose of the Study:

• To identify novel small-molecule inhibitors targeting the c-MET pathway for NSCLC treatment.
• To evaluate the efficacy and drug-like properties of identified c-MET inhibitors.

Main Methods:

• Structure-based and AI-based virtual screening of a compound library.
• In vitro assays to determine c-MET inhibitory activity and NSCLC cell proliferation inhibition.
• ADMET predictions and molecular dynamics simulations for property and stability analysis.

Main Results:

• Six potential c-MET inhibitors were identified; four demonstrated inhibitory activity.
• Compound 2 exhibited potent c-MET inhibition (IC50 = 40.1 nM) and effectively suppressed NSCLC cell proliferation.
• Compound 2 displayed favorable ADMET predictions and stable interactions with key residues (Ala1221, Pro1158, Lys1110) via molecular dynamics simulations.

Conclusions:

• Compound 2 is a promising novel c-MET inhibitor with potential for NSCLC therapy.
• The identified interactions provide insights for further optimization of c-MET inhibitors.