Rafehi Muhammad, Neumann Alexander, Baqi Younis, Malik Enas M, Wiese Michael, Namasivayam Vigneshwaran, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Chemistry I, University of Bonn , 53121 Bonn, Germany.
Department of Chemistry, Faculty of Science, Sultan Qaboos University , PO Box 36, Postal Code 123, Muscat, Oman.
J Med Chem. 2017 Oct 26;60(20):8425-8440. doi: 10.1021/acs.jmedchem.7b00854. Epub 2017 Oct 10.
A homology model of the nucleotide-activated P2YR was created based on the X-ray structures of the P2Y receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP. Significant reduction in agonist potency was observed for all other receptor mutants (Phe111, His184, Ser193, Phe261, Tyr268, Tyr269) predicted to be involved in agonist recognition. An ionic lock between Asp185 and Arg292 that is probably involved in receptor activation interacts with the phosphate groups. The antagonist AR-C118925 and anthraquinones likely bind to the orthosteric site. The updated homology models will be useful for virtual screening and drug design.
基于P2Y受体的X射线结构创建了核苷酸激活型P2YR的同源模型。进行了对接研究，并构建了受体突变体以探究所确定的结合相互作用。预测与核糖相互作用的残基（Arg110）以及核苷酸激动剂的磷酸基团（Arg265、Arg292）或对结合有间接贡献的残基（Tyr288）发生突变会使活性丧失。Y114F、R194A和F261A突变导致四磷酸二腺苷失活，并使UTP的反应降低。对于预测参与激动剂识别的所有其他受体突变体（Phe111、His184、Ser193、Phe261、Tyr268、Tyr269），观察到激动剂效力显著降低。Asp185和Arg292之间可能参与受体激活的离子锁与磷酸基团相互作用。拮抗剂AR-C118925和蒽醌可能结合到正构位点。更新后的同源模型将有助于虚拟筛选和药物设计。
