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

ABSTRACT

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.

KEYWORDS:

• AhR antagonist
• QSAR
• toxicophore
• CALUX
• POP
• linear discriminant analysis

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplementary material for this article can be accessed at: https://doi.org/10.1080/1062936X.2019.1708460.

Additional information

Funding

This work was developed by the Innovative Training Network ‘PROTECTED’: PROTECTion against Endocrine Disruptors; Detection, mixtures, health effects, risk assessment and communication. The project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie actions (MSCA) with grant agreement No. 722634.