Polybrominated diphenyl ethers (PBDEs) are often suspected to activate the signal transduction pathway of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, for the induction of toxicity. Hence, the binding property of PBDEs with AhR is assumed to be associated with the ligand-dependent activation of AhR that may introduce many drug-metabolizing enzymes of genes encoding. However, the binding mechanism and the structural effect of PBDEs on their binding properties of AhR still need to be unraveled for toxicology research. A comprehensive study of the PBDEs-AhR binding mechanism was investigated using an integrated molecular modeling approach with two-dimensional quantitative structure-activity relationships (2D-QSAR), three-dimensional QSAR (3D-QSAR), and molecular docking simulation. Molecular docking revealed the differences in binding domains among 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-AhR complex and two PBDE-AhR complexes. A 2D-QSAR model was developed to analyze the overall structural effects of PBDEs on the binding affinity of AhR. It provided an insight into major physico-chemical properties by multiple linear regression based on genetic algorithm with reasonable results. The 3D-QSAR modeling discovered the detailed interaction features of binding sites, configurations and interaction fields of AhR with different PBDE ligands. This study demonstrated that the descriptors of Smin69 and MoRSEC15 were related to electronic properties and had a great effect on the relative binding affinities. The position of Br substitutions exhibited a significant influence on the interactions between AhR and PBDEs, including halogen interaction, π-S interaction, π-π stacking interaction, and hydrophobic effect. This integrated molecular modeling approach provided a comprehensive analysis of the structural effects of PBDEs on their binding properties with AhR at molecular level.

人们通常怀疑多溴联苯醚（PBDEs）会激活芳烃受体（AhR）（一种配体激活的转录因子）的信号转导途径，以诱导毒性。因此，假定PBDEs与AhR的结合特性与AhR的配体依赖性激活有关，AhR可能引入许多编码基因的药物代谢酶。然而，PBDEs的结合机理和结构对AhR结合特性的影响尚需进行毒理学研究。使用具有二维定量结构-活性关系（2D-QSAR），三维QSAR（3D-QSAR）和分子对接模拟的集成分子建模方法，对PBDEs-AhR结合机理进行了全面研究。分子对接揭示了2,3,7,8-四氯二苯并-对-二恶英（TCDD）-AhR复合物和两个PBDE-AhR复合物之间的结合结构域的差异。建立了一个二维QSAR模型来分析PBDEs对AhR结合亲和力的整体结构影响。通过基于遗传算法的多元线性回归，提供了对主要理化性质的见解，并得出了合理的结果。3D-QSAR建模发现了AhR与不同PBDE配体的结合位点，构型和相互作用场的详细相互作用特征。这项研究表明，通过基于遗传算法的多元线性回归，对主要的理化性质提供了见解，并得出了合理的结果。3D-QSAR建模发现了AhR与不同PBDE配体的结合位点，构型和相互作用场的详细相互作用特征。这项研究表明，通过基于遗传算法的多元线性回归，提供了对主要理化性质的见解，并得出了合理的结果。3D-QSAR建模发现了AhR与不同PBDE配体的结合位点，构型和相互作用场的详细相互作用特征。这项研究表明，Smin69和MoRSEC15与电子特性有关，并且对相对结合亲和力有很大影响。Br取代的位置对AhR和PBDE之间的相互作用具有重要影响，包括卤素相互作用，π-S相互作用，π-π堆积相互作用和疏水效应。这种集成的分子建模方法提供了对多溴二苯醚在分子水平上与AhR结合特性的结构效应的全面分析。