Human Serotonin 5-HT2C G Protein-Coupled Receptor Homology Model from the β2 Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies.
Human Serotonin 5-HT2C G Protein-Coupled Receptor Homology Model from the β2 Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies.
复制标题
β2 肾上腺素受体结构的人血清素 5-HT2C G 蛋白偶联受体同源模型：配体对接和诱变研究。
DOI：
10.1002/qua.23231
复制
发表时间：
2012
影响因子：
2.2
通讯作者：
Booth,Raymond
中科院分区：
文献类型：
--
作者：
Rdova-Sintjago,TaniaCó;Villa,Nancy;Canal,Clinton;Booth,Raymond
Activation of the serotonin (5‐hydroxytryptamine, 5‐HT) 5HT2CG protein‐coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5‐HT2Aand 5‐HT2BGPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5‐HT2Creceptor‐specific ligands. For this reason, a homology model of the 5‐HT2Creceptor was built based on the crystal structure of the human β2adrenoceptor GPCR to delineate molecular determinants of ligand–receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH3)2‐PAT [(1R, 3S)‐(–)‐trans‐1‐phenyl‐3‐N,N‐dimethylamino‐1,2,3,4‐tetrahydronaphthalene], a novel 5‐HT2Cagonist/5‐HT2A/2Binverse agonist, and its secondary [NH(CH3)‐PAT] and primary (NH2‐PAT) amine analogs were studied at the 5‐HT2Cwild type (WT) and D3.32A, S3.36A, and Y7.43A 5‐HT2Cpoint‐mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5‐HT. Modeling results indicated that 5‐HT2Cresidues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point‐mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012
