Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors:: Receptor modeling studies
Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors:: Receptor modeling studies
复制标题
DOI：
10.1021/jm070910s
复制
发表时间：
2008-02-14
影响因子：
7.3
通讯作者：
Glennon, Richard A.
中科院分区：
文献类型：
--
作者：
Dukat, Malgorzata;Mosier, Philip D.;Glennon, Richard A.
基于牛视紫红质结构，构建了100个人类5-HT6血清素受体的图形模型。内源性基于色胺的激动剂5-羟色胺（5-HT; 1）和含苯磺酰色胺衍生的5-HT6受体拮抗剂MS-245 （4a）通过遗传算法自动与100个受体模型对接。对选择性更强的5- ht6受体激动剂EMDT(5)和EMDT相关类似物8的光学异构体，以及MS-245 （4a）相关和含苯磺酰吡啶6和氨基四氟灵7的光学异构体进行了类似的研究。尽管5-HT(1)和MS-245 （4a）与相同的芳香/疏水结合簇相关，但我们发现它们优先结合不同的受体构象，并以不同的结合方向（即姿势）结合。发现EMDT(5)及其类似物具有5- ht位姿/模型，而MS-245 （4a）所鉴定的位姿/模型与含苯磺酰的化合物相同。研究人员发现了参与结合的特定氨基酸残基，并对MS-245的磺胺类似物进行了评价，首次表明磺酰基氧原子的存在增强了受体的亲和力。结果表明，n -1-苯磺酰基的存在与否是色胺相关药物与5-HT6 5-羟色胺受体结合方式的主要决定因素。
A population of 100 graphics models of the human 5-HT6 serotonin receptor was constructed based on the structure of bovine rhodopsin. The endogenous tryptamine-based agonist serotonin (5-HT; 1) and the benzenesulfonyl-containing tryptamine-derived 5-HT6 receptor antagonist MS-245 (4a) were automatically docked with each of the 100 receptor models using a genetic algorithm approach. Similar studies were conducted with the more selective 5-HT6 receptor agonist EMDT (5) and optical isomers of EMDT-related analog 8, as well as with optical isomers of MS-245 (4a)-related and benzenesulfonyl-containing pyrrolidine 6 and aminotetralin 7. Although associated with the same general aromatic/hydrophobic binding cluster, 5-HT (1) and MS-245 (4a) were found to preferentially bind with distinct receptor conformations, and did so with different binding orientations (i.e., poses). A 5-HT pose/model was found to be common to EMDT (5) and its analogs, whereas that identified for MS-245 (4a) was found common to benzenesulfonyl-containing compounds. Specific amino acid residues were identified that can participate in binding, and evaluation of a sulfenamide analog of MS-245 indicates for the first time that the presence of the sulfonyl oxygen atoms enhances receptor affinity. The results indicate that the presence or absence of an N-1-benzenesulfonyl group is a major determinant of the manner in which tryptamine-related agents bind at 5-HT6 serotonin receptors.