天然雌激素生物活性构象的理论分析
首发时间:2011-02-21
摘要:本研究采用模拟退火和分子对接相结合的方法搜索两种天然雌激素17alpha-雌二醇和17beta-雌二醇与雌激素受体alpha亚型作用的生物活性构象,通过模拟退火跳出局域最优解,找到最接近真实状态的构象,同时基于分子对接分析不同构象与雌激素受体活性口袋的作用方式,确定生物活性构象。结果表明模拟退火搜索时能跨越雌二醇构象转化的较高能垒,从而确保在之后的对接研究中获得与已知雌二醇-雌激素受体复合物晶体更吻合的合理空间取向。生物活性构象中3-OH与Arg394、Leu387形成氢键网络,而17-OH则与His524的咪唑环形成氢键作用。
关键词: 环境化学 活性构象 模拟退火 雌激素 结合模式 分子对接
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Theoretical Analysis of Biologically Active Conformations for Natural Estrogens
Abstract:In the present study, simulated annealing was coupled to a molecular docking strategy, FlexX, to explore the biological active conformation of two natural estrogens, 17alpha-estradiol and 17beta-estradiol, in binding with estrogen receptor subtype alpha. Simulated annealing scenario was adapted to help the searching process escape from metastable, locally optimal poses, and obtain the most reliable conformation. Subsequently, molecular docking was used to further analyze the binding mode of estrogen-receptor complexes to distinguish the biologically active conformation. The result indicated that the combined method may find more accurate configuration and orientation for bound estrogens in comparison with the cocrystallized ligand since simulated annealing can provide more heuristic solutions. The phenolic hydroxyl on the A-ring builds strong direct hydrogen bonds to the oxygen atom on carboxylate of GLU353 and azyl on guanidinium group of ARG394, while the one on position 17 of D-ring tends to bind with His524.
Keywords: environmental chemistry active conformation simulated annealing estrogen binding mode molecular docking
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No.4410104568354129****
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