Identification of novel angiogenesis inhibitors.
Vascular endothelial growth factor (VEGF) is a key stimulant of angiogenesis, which is the process of generating new capillary blood vessels. Inhibition of the vascular endothelial growth factor receptor (VEGFR) kinase is known to result in blockage of angiogenesis. A pharmacophore was developed based on the binding of ATP to the hinge region of the kinase domain of VEGFR and a database search of 18,000 compounds was conducted. Selected hits were assessed for their ability to limit the induction of web-like network of capillary tubes by the human umbilical vascular endothelial cells. Two compounds (1 and 4) showed good inhibitory ability to prevent sprouting and closed polygon formation of the tubular networks, promising them to be lead compounds. Compound 4 showed 60% inhibition at 0.05 microM.
Laboratory for In-silico Biology and Drug Discovery, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Jayalakshmi
J
Sridhar
Nagaraju
N
Akula
Dakshanamurthy
D
Sivanesan
Madhusudhanan
M
Narasimhan
Appu
A
Rathinavelu
Nagarajan
N
Pattabiraman
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014470:Umbilical Cord / Q000166:cytology
D020533:Angiogenesis Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor