Discovery of novel vascular endothelial growth factor receptor 2 inhibitors: a virtual screening approach.
A virtual screening approach was performed to develop novel and potent vascular endothelial growth factor receptor 2 inhibitors. The Specs database was filtered by 'rule of five', a pharmacophore model, and docking filter. Sixteen molecules were selected for tube formation assay, a naphthalenol group containing molecule, 12, showed good performance in the study. In the following aortic ring assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 12 was discovered to efficiently inhibit angiogenesis and tumor cell growth. It is the first time to discover naphthalenol scaffold as potent vascular endothelial growth factor receptor 2 inhibitors. Thus, a molecular dynamic simulation process was applied to discover key features of 12 in binding to vascular endothelial growth factor receptor 2. Hydrophobic interactions were discovered to play significant role in the ligand-receptor binding.
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
Lei
L
Zhang
Xuejian
X
Wang
Jinhong
J
Feng
Yuping
Y
Jia
Fuming
F
Xu
Wenfang
W
Xu
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2