Mechanism-based common reactivity pattern (COREPA) modelling of aryl hydrocarbon receptor binding affinity

Abstract

The aryl hydrocarbon receptor is a ligand-activated transcription factor responsive to both natural and synthetic environmental compounds, with the most potent agonist being 2,3,7,8-tetrachlotrodibenzo-p-dioxin. The aim of this work was to develop a categorical COmmon REactivity PAttern (COREPA)-based structure-activity relationship model for predicting aryl hydrocarbon receptor ligands within different binding ranges. The COREPA analysis suggested two different binding mechanisms called dioxin-and biphenyl-like, respectively. The dioxin-like model predicts a mechanism that requires a favourable interaction with a receptor nucleophilic site in the central part of the ligand and with electrophilic sites at both sides of the principal molecular axis, whereas the biphenyl-like model predicted a stacking-type interaction with the aryl hydrocarbon receptor allowing electron charge transfer from the receptor to the ligand. The current model was also adjusted to predict agonistic/antagonistic properties of chemicals. The mechanism of antagonistic properties was related to the possibility that these chemicals have a localized negative charge at the molecule's axis and ultimately bind with the receptor surface through the electron-donating properties of electron-rich groups. The categorization of chemicals as agonists/ antagonists was found to correlate with their gene expression. The highest increase in gene expression was elicited by strong agonists, followed by weak agonists producing lower increases in gene expression, whereas all antagonists (and non-aryl hydrocarbon receptor binders) were found to have no effect on gene expression. However, this relationship was found to be quantitative for the chemicals populating the areas with extreme gene expression values only, leaving a wide fuzzy area where the quantitative relationship was unclear. The total concordance of the derived aryl hydrocarbon receptor binding categorical structure-activity relationship model was 82% whereas the Pearson's coefficient was 0.88.

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

“…These mechanisms imply ligand-dependent differences in the conformation of the AhR complex, and therefore distinct ligand-specific mechanisms of binding of ligands to the AhR would likely exist. In fact, different AhR ligands may bind within the ligand-binding domain (LBD) in distinct sites (59).…”

Naturally Occurring Marine Brominated Indoles Are Aryl Hydrocarbon Receptor Ligands/Agonists

“…While the specific amino acids responsible for these differences remain to be be identified, recent homology modeling, docking and site-directed mutagenesis studies are providing insights into the mechanisms of ligand binding and ligand-dependent AhR activation and may aid in our understanding of these differences in species- and ligand-specificity. 56–59 …”

Comparative gene responses to collected ambient particles in vitro: endothelial responses

“…Halogenated aromatic hydrocarbons and PAHs have been shown to be strong exogenous inducers of CYP1A1 genes by virtue of their ability to bind to and activate the AhR, a ligand-dependent transcription factor (2,12,58). The AhR acts in a wellcharacterized signaling cascade involving occupancy by an AhR agonist (of which there are a large number of structurally diverse chemicals) (12,53,58), which leads to nuclear translocation and its association with the ARNT, which converts the AhR into its high-affinity DNA binding form (12). In addition to stimulating transcription of CYP-related phase I enzymes, the AhR/ARNT complex also induces expression of a variety of phase II enzymes, including specific forms of glutathione S-transferase, quinone reductase, UDP-glucronosyl transferase, and aldehyde dehydrogenase (12,35).…”