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多溴二苯醚类化合物干扰人雌激素受体alpha活性机理的理论研究

ISSN号：0254-6108
期刊名称：《环境化学》
时间：0
分类：TQ457.25[化学工程—农药化工]
作者机构：[1]江苏师范大学化学化工学院,徐州,221116, [2]南京大学环境学院,南京,210093
相关基金：国家自然科学基金项目（20737001）;江苏师范大学博士学位教师科研支持项目（10XLR12）资助.

关键词：多溴二苯醚类化合物, 人雌激素受体α亚型, 分子作用机理, 分子对接, polybrominated diphenyl ether compounds, human estrogen receptor alpha （hERa）,intermolecular interaction mechanism, molecular docking.

中文摘要：

基于分子对接方法探讨了多溴二苯醚（PBDEs）类化合物与人雌激素受体α亚型间的分子作用机理.对多溴二苯醚类化合物是否具有拟雌激素功能的研究得出：可通过对接打分值和化合物结构特征来推测PBDEs母体化合物是否具有拟雌激素活性;对HO-PBDEs,与氨基酸残基GLU53和/或ARG394形成氢键可能是影响其拟雌激素活性的重要因素;对MeO-PBDEs,疏水MeO-位于结合腔的疏水中部有利于拟雌激素活性.从结构及构象分析得出,邻位疏水基（Br-、MeO-）有利于PBDEs类化合物的拟雌激素活性.同时对多溴二苯醚类化合物是否具有抗雌激素功能的结合特征研究发现,表现出抗雌激素活性的部分PBDEs类化合物伸进通常被雌激素受体拮抗剂雷洛昔芬和4-羟基它莫西芬的烷基胺侧链占据的通道,而大多数未表现出抗雌激素活性的PBDEs类化合物的结合模式类似雌激素受体激动剂17β-雌二醇,位于结合腔,没有伸进通道.本研究从化合物结构及化合物在受体内结合的构象特征上解释化合物活性不同的原因,以期能够利用构象分析得到的结果进行筛选.

英文摘要：

Molecular interaction mechanism between polybrominated diphenyl ether （PBDE） compounds and human estrogen receptor alpha （hERa） was explored based on molecular docking. The study for PBDE compounds as hERa agonists revealed that the score values from docking and the structural features should be considered for PBDEs＇ estrogenicity. Hydrogen bond interaction with amino acid residues GLU53 and/or ARG394 might be important for HO-PBDEs＇ estrogenicity. Hydrophobic MeO- that is positioned in the hydrophobic middle region of the binding site is favorable for MeO-PBDEs＇ estrogenicity. Structural and conformational analysis found that hydrophobic substituents （Br-, MeO-）on ortho-position are beneficial to estrogenicity. At the same time, a docking study was carried out to explore the binding modes of PBDE compounds as hERa antagonists. It was found that some of the PBDE compounds with antiestrogenic activity extended into the channel of the estrogen receptor （ER）, which is usually occupied by the alkylamine side chain of the ER antagonists raloxifene （RAL） and 4-hydroxytamoxifen （OHT）. Most PBDE compounds without antiestrogenic activity adopted binding modes similar to that of ER agonist 17β-estradiol （E2）, located in the binding cavity and did not protrude into the channel. The present study explored the structural and conformational requirements of PBDE compounds as hERa agonists/antagonists. It is hoped that further screening can be carried out by analyzing the poses derived from molecular docking.