Browsing by Author "Goya-Jorge, Elizabeth"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Assessing the Chemical-induced Estrogenicity using in Silico and in Vitro Methods
    (Environmental Toxicology and Pharmacology, 2021) Goya-Jorge, Elizabeth; Amber, Mazia; Connolly, Lisa; Barigye, Stephen J.
    Multiple substances are considered endocrine disrupting chemicals (EDCs). However, there is a significant gap in the early prioritization of EDC’s effects. In this work, in silico and in vitro methods were used to model estrogenicity. Two Quantitative Structure-Activity Relationship (QSAR) models based on Logistic Regression and REPTree algorithms were built using a large and diverse database of estrogen receptor (ESR) agonism. A 10-fold external validation demonstrated their robustness and predictive capacity. Mechanistic interpretations of the molecular descriptors (C-026, nArOH,PW5, B06[Br-Br]) used for modelling suggested that the heteroatomic fragments, aromatic hydroxyls, and bromines, and the relative bond accessibility areas of molecules, are structural determinants in estrogenicity. As validation of the QSARs, ESR transactivity of thirteen persistent organic pollutants (POPs) and suspected EDCs was tested in vitro using the MMV-Luc cell line. A good correspondence between predictions and experimental bioassays demonstrated the value of the QSARs for prioritization of ESR agonist compounds.
  • Thumbnail Image
    Item
    Predictive Modeling of Aryl Hydrocarbon Receptor (AhR) Agonism
    (Chemosphere, 2020) Goya-Jorge, Elizabeth; Giner, Rosa M.; Barigye, Stephen J.
    The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of gene expression in metabolic machinery and detoxification systems. In the recent years, this receptor has attracted interest as a therapeutic target for immunological, oncogenic and inflammatory conditions. In the present report, in silico and in vitro approaches were combined to study the activation of the AhR. To this end, a large database of chemical compounds with known AhR agonistic activity was employed to build 5 classifiers based on the Adaboost (AdB), Gradient Boosting (GB), Random Forest (RF), Multilayer Perceptron (MLP) and Support Vector Machine (SVM) algorithms, respectively. The built classifiers were examined, following a 10-fold external validation procedure, demonstrating adequate robustness and predictivity. These models were integrated into a majority vote based ensemble, subsequently used to screen an in-house library of compounds from which 40 compounds were selected for prospective in vitro experimental validation. The general correspondence between the ensemble predictions and the in vitro results suggests that the constructed ensemble may be useful in predicting the AhR agonistic activity, both in a toxicological and pharmacological context. A preliminary structure-activity analysis of the evaluated compounds revealed that all structures bearing a benzothiazole moiety induced AhR expression while diverse activity profiles were exhibited by phenolic derivatives.
  • Thumbnail Image
    Item
    Targeting the Aryl Hydrocarbon Receptor with a Novel set of Triarylmethanes
    (European Journal of Medicinal Chemistry, 2020) Goya-Jorge, Elizabeth; Loones, Nicolas; Barigye, Stephen J.; Gozalbes, Rafael
    The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2[2], [3]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.