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Evaluation of the Influence of Halogenation on the Binding of Bisphenol A to the Estrogen-Related Receptor γ.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-03-11 , DOI: 10.1021/acs.chemrestox.9b00379 Keitaro Suyama 1 , Shuhei Kaneko 2 , Hitoshi Kesamaru 2 , Xiaohui Liu 2 , Ayami Matsushima 2 , Yoshimitsu Kakuta 3 , Takashi Okubo 2 , Kazumi Kasatani 2 , Takeru Nose 1, 2
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-03-11 , DOI: 10.1021/acs.chemrestox.9b00379 Keitaro Suyama 1 , Shuhei Kaneko 2 , Hitoshi Kesamaru 2 , Xiaohui Liu 2 , Ayami Matsushima 2 , Yoshimitsu Kakuta 3 , Takashi Okubo 2 , Kazumi Kasatani 2 , Takeru Nose 1, 2
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Halogenation of organic compounds is one the most important transformations in chemical synthesis and is used for the production of various industrial products. A variety of halogenated bisphenol analogs have recently been developed and are used as alternatives to bisphenol A (BPA), which is a raw material of polycarbonate that has adverse effects in animals. However, limited information is available on the potential toxicity of the halogenated BPA analogs. In the present study, to assess the latent toxicity of halogenated BPA analogs, we evaluated the binding and transcriptional activities of halogenated BPA analogs to the estrogen-related receptor γ (ERRγ), a nuclear receptor that contributes to the growth of nerves and sexual glands. Fluorinated BPA analogs demonstrated strong ERRγ binding potency, and inverse antagonistic activity, similar to BPA. X-ray crystallography and fragment molecular orbital (FMO) calculation revealed that a fluorine-substituted BPA analog could interact with several amino acid residues of ERRγ-LBD, strengthening the binding affinity of the analogs. The ERRγ binding affinity and transcriptional activity of the halogenated BPAs decreased with the increase in the size and number of halogen atom(s). The IC50 values, determined by the competitive binding assay, correlated well with the binding energy obtained from the docking calculation, suggesting that the docking calculation could correctly estimate the ERRγ binding potency of the BPA analogs. These results confirmed that ERRγ has a ligand binding pocket that fits very well to BPA. Furthermore, this study showed that the binding affinity of the BPA analogs can be predicted by the docking calculation, indicating the importance of the calculation method in the risk assessment of halogenated compounds.
中文翻译：
评价卤化对双酚A与雌激素相关受体γ结合的影响。
有机化合物的卤化是化学合成中最重要的转变之一，可用于生产各种工业产品。最近开发了多种卤代双酚类似物，并用作双酚A（BPA）的替代品，BPA是对动物具有不良影响的聚碳酸酯的原料。但是，有关卤代BPA类似物的潜在毒性的信息有限。在本研究中，为评估卤代BPA类似物的潜在毒性，我们评估了卤代BPA类似物与雌激素相关受体γ（ERRγ）的结合和转录活性，雌激素相关受体γ有助于神经和性腺的生长。 。氟化BPA类似物具有很强的ERRγ结合力，并且具有反向拮抗活性，类似于BPA。X射线晶体学和碎片分子轨道（FMO）计算表明，氟取代的BPA类似物可与ERRγ-LBD的多个氨基酸残基相互作用，从而增强了类似物的结合亲和力。卤代BPA的ERRγ结合亲和力和转录活性随卤素原子尺寸和数量的增加而降低。通过竞争性结合测定法确定的IC50值与从对接计算获得的结合能很好地相关，这表明对接计算可以正确估计BPA类似物的ERRγ结合力。这些结果证实了ERRγ具有非常适合BPA的配体结合袋。此外，这项研究表明，可以通过对接计算来预测BPA类似物的结合亲和力，
更新日期：2020-02-27
中文翻译：
评价卤化对双酚A与雌激素相关受体γ结合的影响。
有机化合物的卤化是化学合成中最重要的转变之一，可用于生产各种工业产品。最近开发了多种卤代双酚类似物，并用作双酚A（BPA）的替代品，BPA是对动物具有不良影响的聚碳酸酯的原料。但是，有关卤代BPA类似物的潜在毒性的信息有限。在本研究中，为评估卤代BPA类似物的潜在毒性，我们评估了卤代BPA类似物与雌激素相关受体γ（ERRγ）的结合和转录活性，雌激素相关受体γ有助于神经和性腺的生长。 。氟化BPA类似物具有很强的ERRγ结合力，并且具有反向拮抗活性，类似于BPA。X射线晶体学和碎片分子轨道（FMO）计算表明，氟取代的BPA类似物可与ERRγ-LBD的多个氨基酸残基相互作用，从而增强了类似物的结合亲和力。卤代BPA的ERRγ结合亲和力和转录活性随卤素原子尺寸和数量的增加而降低。通过竞争性结合测定法确定的IC50值与从对接计算获得的结合能很好地相关，这表明对接计算可以正确估计BPA类似物的ERRγ结合力。这些结果证实了ERRγ具有非常适合BPA的配体结合袋。此外，这项研究表明，可以通过对接计算来预测BPA类似物的结合亲和力，
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