Key Laboratory of Resource and Environmental System Optimization, Ministry of Education, North China Electric Power University, Beijing, 102206, China.
College of Environmental Science and Engineering, North China Electric Power University, Beijing, 102206, China.
Environ Sci Pollut Res Int. 2020 Nov;27(31):38805-38818. doi: 10.1007/s11356-020-09668-2. Epub 2020 Jul 6.
In the proposed model, the estrogen activity values and thyroid hormone activity values of PAEs molecules were normalized using the TOPSIS method by eliminating the dimension coefficients, and the comprehensive activity values of estrogen and thyroid hormone were obtained by analyzing the activity of each hormone and assigning the corresponding weight. The five pharmacophore models of hormone combined activity were constructed using the comprehensive activity values. Hypol 1 was the optimal pharmacophore model, showing good predictive power and significance. Then, the DBP, DNOP, and DMP molecules in environmental priority control pollutants were selected as the target molecules to perform common substitution reactions of hydrogen bond donor. Eleven PAEs derivative molecules with significantly reduced combined activity and single activity were screened. In analysis of the differences before and after modification of the docking parameters and amino acid residues before and after modification of PAEs and their derivatives, the reduced closeness between ligand and receptor leads to the decrease of thyroid hormones and estrogen activities. Moreover, the establishment of the models, not only shows that the PAEs hormone activity has certain linear relationships with the physical parameters of molecules but also shows that thyroid hormone activity and estrogen activity of PAEs is consistent with the hormone combined activity. The results confirmed the feasibility of the modified PAEs modification scheme with reduced combined activities of hormones, providing an important theoretical method for the construction of the pharmacophore model of combined activities of hormones and the study of PAEs derivative molecules.
在提出的模型中，通过消除维度系数，使用 TOPSIS 方法对 PAEs 分子的雌激素活性值和甲状腺激素活性值进行归一化，并通过分析每种激素的活性和分配相应的权重来获得雌激素和甲状腺激素的综合活性值。使用综合活性值构建了五种激素联合活性的药效团模型。Hypol 1 是最优药效团模型，表现出良好的预测能力和意义。然后，选择环境优先控制污染物中的 DBP、DNOP 和 DMP 分子作为目标分子，进行氢键供体的常见取代反应。筛选出了 11 种具有显著降低联合活性和单活性的 PAEs 衍生物分子。在分析对接参数修改前后以及 PAEs 和其衍生物修改前后氨基酸残基的差异时，配体与受体之间的接近程度降低导致甲状腺激素和雌激素活性降低。此外，模型的建立不仅表明 PAEs 激素活性与分子的物理参数具有一定的线性关系，而且表明 PAEs 的甲状腺激素活性和雌激素活性与激素联合活性一致。结果证实了用降低的激素联合活性对 PAEs 进行修饰的方案的可行性，为构建激素联合活性的药效团模型和研究 PAEs 衍生物分子提供了重要的理论方法。
