title: Discovery of Potential Orthosteric and Allosteric Antagonists of P2Y1R from Chinese Herbs by Molecular Simulation Methods.
abstract: 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.
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Xu
authors.identifier: 0000-0002-1859-7859
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lu
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Yan-Kun
authors.identifier: 0000-0002-0716-7271
authors.initials: YK
authors.lastname: Chen
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Gang-Gang
authors.identifier: 0000-0002-4175-2263
authors.initials: GG
authors.lastname: Luo
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Lu-di
authors.initials: LD
authors.lastname: Jiang
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Qiao
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Yan-Ling
authors.identifier: 0000-0001-6344-8804
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Xiang