芳香相互作用影响血清素5-羟色胺G蛋白偶联受体的配体结合及功能：受体同源性建模、配体对接及分子动力学结果经实验研究验证。
Aromatic interactions impact ligand binding and function at serotonin 5-HT G protein-coupled receptors: Receptor homology modeling, ligand docking, and molecular dynamics results validated by experimental studies.
作者信息
Córdova-Sintjago Tania, Villa Nancy, Fang Lijuan, Booth Raymond G
机构信息
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA.
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 USA ; Center for Drug Discovery, Departments of Pharmaceutical Sciences, and, Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115 USA.
出版信息
Mol Phys. 2014 Jan 1;112(3-4):398-407. doi: 10.1080/00268976.2013.833656.
Abstract
The serotonin (5-hydroxytryptamine, 5-HT) 5-HT G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ~75% transmembrane (TM) sequence identity. Agonists for 5-HT receptors are under development for psychoses, whereas, at 5-HT receptors, antipsychotic effects are associated with antagonists-in fact, 5-HT agonists can cause hallucinations and 5-HT agonists cause cardiotoxicity. It is known that 5-HT TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function, however, ligand interactions with these residues at the 5-HT receptor has not been reported. To predict and validate molecular determinants for 5-HT-specific activation, results from receptor homology modeling, ligand docking, and molecular dynamics (MD) simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT receptors.
摘要
血清素（5-羟色胺，5-HT）5-HT G蛋白偶联受体（GPCR）家族由2A、2B和2C型组成，它们具有约75%的跨膜（TM）序列同一性。5-HT受体激动剂正在开发用于治疗精神病，而在5-HT受体方面，抗精神病作用与拮抗剂相关——事实上，5-HT激动剂可导致幻觉，且5-HT激动剂会引起心脏毒性。已知5-HT TM6残基W6.48、F6.51和F6.52会影响配体结合和功能，然而，尚未有关于配体与5-HT受体上这些残基相互作用的报道。为了预测和验证5-HT特异性激活的分子决定因素，将受体同源建模、配体对接和分子动力学（MD）模拟研究的结果与野生型以及W6.48A、F6.51A和F6.52A点突变的5-HT受体上配体结合和功能的实验结果进行了比较。
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