Elucidating the aryl hydrocarbon receptor antagonism from a chemical-structural perspective

The aryl hydrocarbon receptor (AhR) plays an important role in several biological processes such as reproduction, immunity and homoeostasis. However, little is known on the chemical-structural and physicochemical features that influence the activity of AhR antagonistic modulators. In the present report, in vitro AhR antagonistic activity evaluations, based on a chemical-activated luciferase gene expression (AhR-CALUX) bioassay, and an extensive literature review were performed with the aim of constructing a structurally diverse database of contaminants and potentially toxic chemicals. Subsequently, QSAR models based on Linear Discriminant Analysis and Logistic Regression, as well as two toxicophoric hypotheses were proposed to model the AhR antagonistic activity of the built dataset. The QSAR models were rigorously validated yielding satisfactory performance for all classification parameters. Likewise, the toxicophoric hypotheses were validated using a diverse set of 350 decoys, demonstrating adequate robustness and predictive power. Chemical interpretations of both the QSAR and toxicophoric models suggested that hydrophobic constraints, the presence of aromatic rings and electron-acceptor moieties are critical for the AhR antagonism. Therefore, it is hoped that the deductions obtained in the present study will contribute to elucidate further on the structural and physicochemical factors influencing the AhR antagonistic activity of chemical compounds.芳基烃受体（aryl hydrocarbon receptor, AhR）在生殖、免疫与体内稳态等多种生物学过程中发挥关键作用。然而，当前学界对影响芳基烃受体拮抗调节剂活性的化学结构与理化性质特征的认知仍较为有限。本研究依托化学激活荧光素酶基因表达（AhR-CALUX）生物检测法开展体外芳基烃受体拮抗活性评价，并结合广泛的文献综述，旨在构建一个结构多样性的污染物与潜在有毒化学品数据库。随后，本研究提出了基于线性判别分析（Linear Discriminant Analysis）与逻辑回归（Logistic Regression）的定量结构-活性关系（Quantitative Structure-Activity Relationship, QSAR）模型，以及两项毒性药效团假说（toxicophoric hypotheses），以对所构建数据集的芳基烃受体拮抗活性进行建模。所有QSAR模型均经过严格验证，各项分类参数均表现出令人满意的性能。同理，本研究使用包含350个诱饵分子（decoys）的多样化数据集对毒性药效团假说进行验证，结果证实其具备良好的稳健性与预测能力。对QSAR模型与毒性药效团模型的化学解读表明，疏水约束、芳香环的存在以及电子受体基团，是影响化合物芳基烃受体拮抗活性的核心因素。因此，本研究所得的推论有望为进一步阐明调控化合物芳基烃受体拮抗活性的结构与理化因素提供有力支撑。