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.

中文翻译：

---

从化学结构的角度阐明了芳烃受体的拮抗作用。

芳基烃受体（AhR）在几种生物学过程（例如繁殖，免疫和同稳态）中起着重要作用。但是，关于影响AhR拮抗调节剂活性的化学结构和物理化学特征知之甚少。在本报告中，进行了基于化学激活的萤光素酶基因表达（AhR-CALUX）生物测定的体外AhR拮抗活性评估，并进行了广泛的文献综述，目的是建立结构多样的污染物和潜在有毒化学物质数据库。随后，提出了基于线性判别分析和逻辑回归的QSAR模型，以及两个毒理学假设，以对所建立数据集的AhR拮抗活性进行建模。严格验证了QSAR模型，对所有分类参数均产生令人满意的性能。同样，使用一组350个诱饵对毒理学假说进行了验证，证明了足够的鲁棒性和预测能力。QSAR和毒理学模型的化学解释表明，疏水约束，芳香环和电子受体部分的存在对于AhR拮抗作用至关重要。因此，希望本研究获得的推论将有助于进一步阐明影响化合物的AhR拮抗活性的结构和物理化学因素。表现出足够的鲁棒性和预测能力。QSAR和毒理学模型的化学解释表明，疏水约束，芳香环和电子受体部分的存在对AhR拮抗作用至关重要。因此，希望本研究获得的推论将有助于进一步阐明影响化合物的AhR拮抗活性的结构和物理化学因素。表现出足够的鲁棒性和预测能力。QSAR和毒理学模型的化学解释表明，疏水约束，芳香环和电子受体部分的存在对AhR拮抗作用至关重要。因此，希望本研究获得的推论将有助于进一步阐明影响化合物的AhR拮抗活性的结构和物理化学因素。