Identification of Potential c-MET Inhibitors from Natural Product Library by Virtual Screening, Molecular Dynamics and MM/PBSA Approach
Makaleler > Tam Makale · 2026
Yazarlar: Emre Can Buluz
International Journal of Advances in Engineering and Pure Sciences, Uluslararası, 2026, cilt 38, ss 71-84
DOI: 10.7240/jeps.1740666
Özet
c-MET is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drug development. Dysregulation of the c-MET/HGF pathway has been implicated in various human proliferative disorders. Crizotinib, initially developed as a selective c-MET inhibitor, is now recognized as a multitargeted tyrosine kinase inhibitor (TKI). Natural products remain a valuable source for drug discovery. In this study, a total of 153,019 natural product and natural product-like molecules collected from eight major libraries were screened to identify novel c-MET inhibitors using an integrated workflow combining virtual screening, ADME/toxicity filtering, molecular dynamics (MD) simulations, and MM/PBSA free energy analysis. A total of 30,534 molecules passing the Lipinski, PAINS and Brenk filters in the KNIME workflow were used in the virtual screening. After filtration based on the Veber, Egan, Ghose, and Muegge criteria, 148 molecules exhibited better binding scores than Crizotinib (−10.40 kcal/mol). Molecules with binding energies lower than –10.40 kcal/mol were carried forward for further analyses. Subsequent ProTox-II screening reduced the pool to seven non-toxic candidates. The two molecules among the selected seven that exhibited the highest binding scores were ZINC98363582 and ZINC98365604, each with a value of –10.70 kcal/mol. MD simulations (30 ns) demonstrated that all protein–ligand complexes maintained structural stability, showing average RMSD values between 0.125–0.20 nm, comparable to or better than the Crizotinib complex. MM/PBSA calculations revealed that several candidates exhibited markedly superior binding affinities relative to Crizotinib (−47.648 kJ/mol). Notably, ZINC98063878 displayed the strongest binding free energy (−153.481 kJ/mol), followed by NPA009357 (−112.425 kJ/mol) and NPA032454 (−109.835 kJ/mol). These values indicate significantly enhanced thermodynamic favorability driven by strong van der Waals and electrostatic contributions. Overall, the molecules ZINC98063878, NPA009357, NPA032454, ZINC98363582, and ZINC98365604 emerged as promising natural product-derived c-MET inhibitor candidates, outperforming the clinical reference molecule (Crizotinib) in both stability and predicted binding energy. These findings highlight their potential for further in vitro and in vivo evaluation toward developing next-generation c-MET–targeted anticancer agents.