Ultra-Large Pharmacophore-Guided Screening Identifies Novel c-MET Inhibitors with Favorable Energetics and Residue-Level Interaction Signatures

Abstract

The receptor tyrosine kinase c-MET plays a pivotal role in oncogenic signaling processes associated with tumor proliferation, metastasis, and therapeutic resistance, making it an attractive molecular target for anticancer drug discovery. Although several inhibitors have been developed, the search for novel c-MET inhibitors with improved interaction characteristics remains essential. Building upon our previous computational investigation of c-MET inhibitors, this study employed a large-scale pharmacophore-guided virtual screening approach to identify novel candidate compounds targeting the c-MET catalytic domain. A validated pharmacophore model derived from a reference inhibitor was used to screen approximately 103,302,052 compounds from the PubChem database, followed by hierarchical filtering, molecular docking, molecular dynamics simulations, binding free-energy estimation, and per-residue energy decomposition analysis to elucidate interaction contributions at the amino acid level. Two compounds, PubChem-154859854 and PubChem-9038296, emerged as promising lead candidates, demonstrating favorable binding affinities, stable dynamic behaviour, and energetically favorable complex formation compared with the reference ligand. Notably, residue decomposition analysis identified MET1211 as a major energetic contributor to ligand stabilization, highlighting its critical role within the catalytic pocket. Overall, the identified compounds represent potential novel c-MET inhibitors and provide a computational foundation for future experimental validation toward targeted cancer therapy