Zhang Xu, Lu Fang, Chen Yan-Kun, Luo Gang-Gang, Jiang Lu-di, Qiao Lian-Sheng, Zhang Yan-Ling, Xiang Yu-Hong
Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
Department of Chemistry, Capital Normal University, Beijing 100048, China.
Evid Based Complement Alternat Med. 2016;2016:4320201. doi: 10.1155/2016/4320201. Epub 2016 Aug 21.
P2Y1 receptor (P2Y1R), which belongs to G protein-coupled receptors (GPCRs), is an important target in ADP-induced platelet aggregation. The crystal structure of P2Y1R has been solved recently, which revealed orthosteric and allosteric ligand-binding sites with the details of ligand-protein binding modes. And it suggests that P2Y1R antagonists, which recognize two distinct sites, could potentially provide an efficacious and safe antithrombotic profile. In present paper, 2D similarity search, pharmacophore based screening, and molecular docking were used to explore the potential natural P2Y1R antagonists. 2D similarity search was used to classify orthosteric and allosteric antagonists of P2Y1R. Based on the result, pharmacophore models were constructed and validated by the test set. Optimal models were selected to discover potential P2Y1R antagonists of orthosteric and allosteric sites from Traditional Chinese Medicine (TCM). And the hits were filtered by Lipinski's rule. Then molecular docking was used to refine the results of pharmacophore based screening and analyze the binding mode of the hits and P2Y1R. Finally, two orthosteric and one allosteric potential compounds were obtained, which might be used in future P2Y1R antagonists design. This work provides a reliable guide for discovering natural P2Y1R antagonists acting on two distinct sites from TCM.
P2Y1受体（P2Y1R）属于G蛋白偶联受体（GPCRs），是ADP诱导血小板聚集的重要靶点。P2Y1R的晶体结构最近已得到解析，揭示了其正构和别构配体结合位点以及配体与蛋白质结合模式的细节。这表明识别两个不同位点的P2Y1R拮抗剂可能具有有效且安全的抗血栓形成特性。在本文中，利用二维相似性搜索、基于药效团的筛选和分子对接来探索潜在的天然P2Y1R拮抗剂。二维相似性搜索用于对P2Y1R的正构和别构拮抗剂进行分类。基于该结果构建药效团模型，并通过测试集进行验证。选择最佳模型来从中药中发现正构和别构位点的潜在P2Y1R拮抗剂。然后根据Lipinski规则对命中的化合物进行筛选。接着使用分子对接来优化基于药效团筛选的结果，并分析命中化合物与P2Y1R的结合模式。最后，获得了两种正构和一种别构潜在化合物，它们可能用于未来P2Y1R拮抗剂的设计。这项工作为从中药中发现作用于两个不同位点的天然P2Y1R拮抗剂提供了可靠的指导。
