羟基化多氯联苯间接雌激素效应的对接和QSAR研究

E. Heimstad, P. Andersson
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引用次数: 9

摘要

利用多变量方法和半经验描述符,建立了羟基化多氯联苯(OH-PCBs)抑制人雌激素硫转移酶(hEST)的定量构效关系(QSAR)。QSAR模型包括10种选择的oh - pcb,最近报道的实验抑制hEST的能力和17个理化参数。交叉验证的解释方差为0.71,表明模型具有较高的预测能力。最重要的参数是亚分子电子参数,如部分原子电荷和亲核电子密度。天然底物雌二醇和oh -多氯联苯已被认为通过非竞争性结合到一个尚未确定的变弹性位点来抑制hEST。利用CAST和GRAMM程序,对小鼠雌激素硫转移酶(mEST)晶体结构中潜在的变构结合位点及其同源模型进行了研究和讨论。总的来说,使用GRAMM的最丰富的对接位点与CAST定义的口袋一致。当hEST活性二聚体可用时,应验证这些初步结果并进行更详细的研究。结果表明,其他类似的污染物也可能干扰雌二醇的磺化反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Docking and QSAR studies of an indirect estrogenic effect of hydroxylated PCBs
A quantitative structure-activity relationship (QSAR) of hydroxylated polychlorinated biphenyls (OH-PCBs) potency to inhibit human estrogen sulfotransferase (hEST), was modeled using multivariate methods and calculated semi-empirical descriptors. The QSAR model included 10 selected OH-PCBs, recently reported experimental inhibition potencies of hEST and 17 physico- chemical parameters. The cross-validated explained variance of 0.71 indicates a high predictive capacity of the model. The most important parameters were sub-molecular electronic parameters, such as partial atomic charges and nucleophilic electron densities. The natural substrate estradiol and OH-PCBs have been suggested to inhibit hEST by non-competitive binding to a not yet identified allosteric site. Potential allosteric binding sites in the crystal structure of mouse estrogen sulfotransferase (mEST) and in a homology model of hEST were investigated and discussed using the programs CAST and GRAMM. In general, the most abundant docking sites using GRAMM were in agreement with pockets defined by CAST. These preliminary results should be verified and more detailed studies undertaken when the active dimer of hEST is available. The results indicate that other similar pollutants may well interfere with the sulfonation of estradiol.
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