期刊
CANADIAN JOURNAL OF CHEMISTRY
卷 93, 期 3, 页码 311-316出版社
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/cjc-2014-0429
关键词
P2Y(12) receptor antagonists; pharmacophore modeling; docking; virtual screening; traditional Chinese medicine
资金
- National Natural Science Foundation of China [81173522]
P2Y(12), a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y(12) receptor is a popular drug target. After the recent resolution of the P2Y(12) receptor's crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophore-based screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y(12) receptor antagonists from traditional Chinese herbs.
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