Discovery of VEGFR2 inhibitors by integrating naïve Bayesian classification, molecular docking and drug screening approaches.

The high morbidity and mortality of cancer make it one of the leading causes of global death, thus it is an urgent need to develop effective drugs for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR2) acts as a central modulator of angiogenesis, and is therefore an important pharmaceutical target for developing anti-angiogenic agents. In this study, ligand-based naïve Bayesian (NB) models and structure-based molecular docking were combined to develop a virtual screening (VS) pipeline for identifying potential VEGFR2 inhibitors from FDA-approved drugs. The best validated naïve Bayesian model (NB-c) gave Matthews correlation coefficients of 0.966 and 0.951 for the test set and external validation set, respectively. 1841 FDA-approved drugs were sequentially screened by the optimal model NB-c and molecular docking module LibDock. By analyzing the results of VS, 9 top ranked drugs with EstPGood value ≥ 0.6 and LibDock Score ≥ 120 were chosen for biological validation. VEGFR2 kinase assay results demonstrated that flubendazole, rilpivirine and papaverine showed VEGFR2 inhibitory activities with IC values ranging from 0.47 to 6.29 μM. Binding mode analysis with CDOCKER revealed the action mechanism of the 3 hit drugs binding to VEGFR2. In summary, we not only proposed an integrated VS pipeline for potential VEGFR2 inhibitors screening, but also identified 3 FDA-approved drugs as novel VEGFR2 inhibitors, which could be used to design and develop new antiangiogenic agents.