Discovery of a novel VEGFR2 inhibitor using integrated structure-based docking study and functional validation: potential applications in targeted cancer therapy

Cancer remains a predominant cause of mortality worldwide, with conventional therapies often limited by adverse side effects and the development of drug resistance. Targeting receptor tyrosine kinases (RTKs), especially vascular endothelial growth factor receptor 2 (VEGFR2), presents a viable strategy due to its pivotal role in tumor angiogenesis. This study employed an integrative approach combining structure-based docking study, kinase inhibition assays, and cytotoxicity evaluations to identify novel VEGFR2 inhibitors. A Protein Kinase Diversity Set library comprising over 2,000 compounds was screened via molecular docking against the VEGFR2 crystal structure. The highest-ranking candidates were subjected to detailed binding interaction analyses. Cytotoxicity assays demonstrated significant anti-proliferative effects in VEGFR2-overexpressing U87 cells, while enzymatic assays confirmed one novel compound's potency in inhibiting VEGFR2 kinase activity. Redocking simulations focusing on the receptor's active site ensured comprehensive conformational exploration of ligand binding modes. Our results identify a promising lead compound as a novel inhibitor of VEGFR2, with potential applicability as an anti-angiogenic and anticancer therapeutic agent, warranting further optimization.