Discovery novel VEGFA inhibitors through structure-based virtual screening and verify the ability to inhibit the proliferation, invasion and migration of gastric cancer

Abstract

This paper aims to screen small molecule inhibitors 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) targeting vascular endothelial growth factor A (VEGFA) through structure based virtual screening and molecular dynamics simulation, and verify the effect of anti gastric cancer.First, Based on Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the candidate small-molecule compounds targeting VEGFA were screened by a molecular docking method using Computer-Aided Drug Design. Second, CCK8 was used to determine the effect of three commercially available candidate drugs on the proliferation activity of HGC27 and AGS. PGG was selected for further cell cloning, invasion, migration and apoptosis experiments. Finally, the complex system of three compounds and VEGFA was analyzed by molecular dynamics simulation.According to the ranking of the scoring function, the selected small molecular compounds are PGG, 2,3,4,6-tetra-O-galactosyl-D-glucopyranoside, rutin, quercetin-5,3-d-galactoside and 1F-Fructofuranosylnystose (1FF). CCK8 showed that PGG had the best inhibitory effect on the proliferation of AGS and HGC27 cells, and it was concentration and time dependent. Treatment of AGS and HGC27 with IC50 PGG can significantly inhibit the cloning of HGC27 and AGS, block their invasion and migration, and induce their apoptosis. Molecular dynamics simulation experiments showed that the binding of PGG to VEGFA target protein was better than that of other two small molecular compounds, which was consistent with the results of molecular docking and biological activity experiments.