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.

Exploring the structural aspects of ureido-amino acid-based APN inhibitors: a validated comparative multi-QSAR modelling study

“…In the current study, the LDA was performed in STATISTICA version 7 [50] via a stepwise technique of variable selection using F = 4.0 criteria for variable inclusion and F = 3.9 for the variable exclusion [51]. In order to validate the robustness of the LDA model, different receiver operating characteristic (ROC)-based validation metrics such as sensitivity, specificity, precision, accuracy, F-measure, Matthew's correlation coefficient (MCC), along with Wilk's lambda (λ), chi-square test value (χ 2 ), etc., were calculated [51][52][53].…”

Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs

“…Classical medicinal approaches rely on orthosteric and allosteric inhibitors for direct target inhibition. Approaches such as (a) preferential protein subtype selectivity [180,181], or species-specific selectivity [182,183], (b) cyclization or rigidification in inhibitor design [184][185][186][187][188][189], (c) targeting heterodimeric proteins or receptors [12,190,191]), (d) identification of toxicophore to pharmacophore [192][193][194][195], (e) repurposing of drugs of clinical agents [196], (f) inverse screening [197,198]), and (g) exploration of natural phytochemicals [199][200][201] have gained interest in the recent decade. As these approaches focus on small molecule inhibitors (SMIs) and their related modes of action; therefore, often have issues that are typical with occupancy-driven pharmacology (shown in Figure 1A), such as (a) frequent occurrence of resistance after prolonged use and, (b) require a higher degree of potency to achieve full inhibition of protein of interest (POI).…”

Human Adult Microbiota in a Static Colon Model: AhR Transcriptional Activity at the Crossroads of Host–Microbe Interaction

“…This allowed for the simultaneous assessment of the AhR activity, and the potential cytotoxicity caused by the treatments. For AhR-T47D and AhR-HepG2 cell lines, the cytotoxicity was studied as detailed previously [47]. The MTT formazan absorbance was read in all cases at 550/630 nm using an ELX800TM microplate reader spectrophotometer (Agilent BioTek Inc., Winooski, VT, USA).…”