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

Junmin Dong Xiaohua Hao ^*

• Beijing Shijitan Hospital, Capital Medical University, Beijing, China

The vascular endothelial growth factor receptor 2 (VEGFR-2) and the mesenchymal-epithelial transition factor (c-Met) signaling pathways synergistically contribute to the pathogenesis and progression of various cancers. Therefore, VEGFR-2/c-Met dual-target inhibitors have the potential to effectively inhibit angiogenesis, impede tumor progression, and are expected to offer better effects in overcoming tumor cell resistance compared to the inhibition of a single target. 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. Following the screening process, 18 hit compounds were identified. Among them, compound17924 and compound4312 possessed the best inhibitory potential. Molecular dynamics (MD) simulation and MM/PBSA calculation were followed to determine the stability of protein-molecular interaction. Analysis of results revealed that compound17924 and compound4312 exhibited superior binding free energies to VEGFR-2 and c-Met compared with the positive ligands. Both two compounds were promising candidates for further drug development and could potentially serve as improved alternatives of cancer therapeutics.