Discovery of VEGFR inhibitors through virtual screening and energy assessment

Abstract

AbstractVascular endothelial growth factor receptor‐2 (VEGFR‐2) is crucial in promoting tumor angiogenesis and cancer metastasis. Thus, inhibition of VEGFR‐2 has appeared as a good tactic for cancer treatment. To find out novel VEGFR‐2 inhibitors, first, the PDB structure of VEGFR‐2, 6GQO, was selected based on atomic nonlocal environment assessment (ANOLEA) and PROCHECK assessment. 6GQO was then further used for structure‐based virtual screening (SBVS) of different molecular databases, including US‐FDA approved drugs, US‐FDA withdrawn drugs, may bridge, MDPI, and Specs databases using Glide. Based on SBVS, receptor fit, drug‐like filters, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of 427877 compounds, the best 22 hits were selected. From the 22 hits, hit 5 complex with 6GQO was put through molecular mechanics/generalized born surface area (MM/GBSA) study and hERG binding. The MM/GBSA study revealed that hit 5 possesses lesser binding free energy with more inferior stability in the receptor pocket than the reference compound. The VEGFR‐2 inhibition assay of hit 5 disclosed an IC50 of 165.23 nM against VEGFR‐2, which can be possibly enhanced through structural modifications.