State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, PR China.
Toxicol Appl Pharmacol. 2012 Dec 15;265(3):300-7. doi: 10.1016/j.taap.2012.08.030. Epub 2012 Sep 6.
Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q²) was 0.571 and non-cross-validation correlation coefficient (r²) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results.
一些最近的报告表明，羟基化多溴二苯醚（HO-PBDEs）可能会干扰甲状腺激素的动态平衡。为了阐明 HO-PBDEs 对甲状腺激素活性的结构特征以及 HO-PBDEs 与甲状腺激素受体（TR）之间的结合模式，基于 3D-QSAR、分子对接和分子动力学（MD）方法，研究了一系列 HO-PBDEs 对甲状腺受体β的激素活性。使用比较分子相似性指数分析（CoMSIA）方法获得了基于配体和受体的 3D-QSAR 模型。具有区域聚焦的最佳 CoMSIA 模型产生了令人满意的统计结果：留一法交叉验证相关系数（q²）为 0.571，非交叉验证相关系数（r²）为 0.951。此外，内部验证结果，如自举法、留多位点交叉验证和逐步乱序以及外部验证表明了最佳模型的合理性和良好的预测能力。此外，分子对接阐明了化合物的构象和对接口袋中的关键氨基酸残基，MD 模拟进一步确定了结合过程并验证了对接结果的合理性。
