Pharmacophore screening, molecular docking, and MD simulations for identification of VEGFR-2 and c-Met potential dual inhibitors.

Introduction: The vascular endothelial growth factor receptor 2 (VEGFR-2) and the mesenchymal-epithelial transition factor (c-Met) are critical in the pathogenesis and progression of various cancers by synergistically contributing to angiogenesis and tumor progression. The development of dual-target inhibitors for VEGFR-2 and c-Met holds promise for more effective cancer therapies that could overcome tumor cell resistance, a limitation often observed with inhibitors targeting a single receptor. Methods: In this study, a computational virtual screening approach involving drug likeness evaluation, pharmacophore modeling and molecular docking was employed to identify VEGFR-2/c-Met dual-target inhibitors from ChemDiv database. Subsequent molecular dynamics (MD) simulations and MM/PBSA calculations were conducted to assess the stability of the protein-ligand interactions. Results: From the virtual screening process, 18 hit compounds were identified to exhibit potential inhibitory activity against VEGFR-2 and c-Met. Among them, compound17924 and compound4312 possessed the best inhibitory potential according to our screening criteria. Discussion: The analysis of the MD simulation results indicated that compound17924 and compound4312 showed superior binding free energies to both VEGFR-2 and c-Met when compared to the positive ligands. These findings suggested that both compounds were promising candidates for further drug development and could potentially serve as improved alternatives of cancer therapeutics.