Repurposing of FDA-approved and investigational drugs as MET-kinase inhibitors against NSCLC: A combined in-silico modeling and machine learning approach

Background and Aims: The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase plays a pivotal role in cancer therapy. However, mutations such as D۱۲۲۸V can diminish the effectiveness of current inhibitors. In continuation to our interest for in silico assessment of oncotargets, this study sought to identify FDA-approved and investigational drugs that are likely capable of inhibiting both wild-type MET and its D۱۲۲۸V mutant form against non-small cell lung cancer (NSCLC). Methods: A dataset comprising ۶۳۹ tyrosine kinase inhibitors with NSCLC-related cell growth inhibitory effects (IC۵۰s) from ChEMBL (https://www.ebi.ac.uk/chembl/) was curated, applying a ۱۰۳ nM bioactivity threshold as a cut-off point and balanced with DUD-E decoy molecules. Several machine learning models including LightGBM, XGBoost, and Random Forest, were utilized along with different molecular fingerprints. According to the obtained results, LightGBM with extended connectivity fingerprint (ECFP) emerged as the most effective model with satisfying metrics (accuracy ۰.۹۳, sensitivity ۰.۹۶, and specifity ۰.۸۷). The top-ranked model screened ۶۲۶۳ molecules from DrugBank, identifying ۲۳۳ as potentially active. Subsequent drug-likeness filtering (Lipinski rule of ۵ and rotatable bonds ۱۰), conferred ۱۷۳ candidates that were docked into the catalytic site of wild-type MET receptor. Of these, ۲۸ outperformed the reference co-crystal inhibitor Savolitinib and were subjected to molecular docking to the D۱۲۲۸V mutant. Results: Seventeen molecules demonstrated enhanced binding profile to the D۱۲۲۸V mutant catalytic site, with enhanced free binding energies (ΔΔGbs -۰.۰۵ to -۰.۹۵ kcal/mol) with regard to the wild-type energies. Key examples included SAR-۱۲۵۸۴۴ (ΔΔGb -۰.۳۸ kcal/mol) and Edralbrutinib (ΔΔGb -۰.۹۵ kcal/mol). Conclusion: This study underscores the repurposing potential of dual MET inhibitors, such as SAR-۱۲۵۸۴۴ and Palbociclib against NSCLC. The outputs of the current study suggests opportunities for drug repurposing in cancer treatment. Although results of this computational study provided a few promising molecules as a promising MET inhibitors, robust wet-lab experiments seem necessary to achieve desirable biological and clinical effects.

کلیدواژه ها:

NSCLC ، MET Kinase ، Drug Repurposing ، Machine