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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors.
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Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors.

机译：计算分析的均聚和异五聚体5-HT3受体的配体识别位点。

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摘要

Inhibition of the 5-hydroxytryptamine receptor (5-HT(3)R), a member of the Cys-loop superfamily of Ligand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. With respect to the many other drugs already in use, such as the first generation 5-HT(3)R antagonist granisetron, palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potency towards the 5-HT(3)Rs. Five different receptor monomers, the 5-HT(3)R A-E, have been identified although the A and B subunits are the only known to build functional receptors, the homopentameric 5-HT(3A)R and the heteropentameric 5-HT(3B-A)R (with BBABA subunit arrangement). At present, however, no three-dimensional structure has been reported for any of the 5-HT(3)R subunits. To understand the binding properties of agonists and antagonists, models of the extracellular portion of the 5-HT(3)R A and B subunits are built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of the known three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results of docking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron into the modelled homomeric and heteromeric 5-HT(3)R binding interfaces, provide a possible rationalization both of the higher potency of palonosetron with respect to other antagonists, and of its previously reported allosteric binding and positive cooperativity properties.
机译：5-羟基色胺受体（5-HT（3）R），​​配体门离子通道（LGIC）的Cys环超家族的成员的抑制作用已被认为具有重要的止吐作用。对于已经使用的许多其他药物，例如第一代5-HT（3）R拮抗剂granisetron，第二代拮抗剂palonosetron，显然显示出对5-HT（3）R的优越抑制作用。虽然A和B亚基是唯一已知的能建立功能性受体的同位五聚体5-HT（3A）R和异五聚体5-HT（3B），但已鉴定出五种不同的受体单体5-HT（3）R AE -A）R（具有BBABA亚基排列）。但是，目前，还没有任何3-HT（3）R亚基的三维结构报告。为了了解激动剂和拮抗剂的结合特性，在已知的三种基础上，构建了5-HT（3）RA和B亚基的细胞外部分模型，并将其组装成受体（同型和异型）五聚体结构烟碱乙酰胆碱受体（nACh-R）的三维结构。天然激动剂5-羟色胺与拮抗剂帕洛诺司琼和格拉司琼对接的建模同聚物和异聚5-HT（3）R结合界面的对接研究结果，提供了帕洛诺司琼相对于其他拮抗剂的更高效力的合理化解释，以及其先前报道的变构结合和积极的合作性质。

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