title: Discovery of loperamide as an antagonist of angiopoietin1 and angiopoietin2 by virtual screening.
abstract: The angiopoietin-Tie2 binding and related signal transduction pathways are crucial for vascular angiogenesis, blood vessel integrity and maturation. In this study, we preformed a virtual screening of small molecules targeting to Tie2. The binding site was selected at the extracellular ligand binding region of Tie2, rather than its conventional endocellular ATP binding region. It was found that loperamide, a widely-used antidiarrhea drug, was among the top hits. The binding between loperamide and Tie2 was confirmed by surface plasmon resonance (SPR) assay. Loperamide competitively inhibited the binding of both angiopoietin1 and angiopoietin2. These results indicate that loperamide is an antagonist of angiopoietin1 and angiopoietin2.
authors.affiliation: College of Food Science and Biotechnology, Zhejiang Gongshang University, Food Safety Key Lab of Zhejiang Province, Hangzhou 310035, China. gongxingwen@163.com
authors.forename: Xing Wen
authors.initials: XW
authors.lastname: Gong
authors.forename: Jun Hua
authors.initials: JH
authors.lastname: Mai
authors.forename: Yu Hong
authors.initials: YH
authors.lastname: Xu
mesh_terms: D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000930:Antidiarrheals / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008139:Loperamide / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000930:Antidiarrheals; D008024:Ligands; D011994:Recombinant Proteins; D008139:Loperamide; D042787:Receptor, TIE-2