Discovery of novel VEGFR-2 inhibitors through virtual screening, synthesis and bioactivity evaluation.

Vascular endothelial growth factor receptor 2 (VEGFR-2) is an attractive antitumor target. By effectively inhibiting the overexpression of VEGFR-2, it suppresses the abnormal angiogenesis occurring within tumors. Although some inhibitors targeting VEGFR-2 have been identified, the drug resistance is an unignorable disadvantage to make the urgent need of new structure inhibitors. In this study, an innovative approach involving vast chemical space similarity searching was applied using sunitinib as a template to generate a series of structurally novel and synthetically accessible small molecules. A series robust virtual screening methods were employed to discover promising compounds for synthesis and evaluation of their kinase inhibitory activity against VEGFR-2. The results demonstrated that two of these compounds, GL-3 (IC50 = 5.44 μM) and GL-1 (IC50 = 13.4 μM), exhibited inhibitory activity against VEGFR-2. Subsequently, molecular dynamics simulations were conducted to investigate the interaction mechanisms of these active molecules with VEGFR-2. In summary, this study offers novel perspectives on the development of VEGFR-2 inhibitors and offers an innovative strategy for discovering novel anticancer drugs.