Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Li, Fēi; Li, Xuehua; Liu, Xiaoli; Zhang, Linbao; You, Liu; Zhao, Jianmin; Wu, Huifeng

doi:10.1016/j.etap.2011.09.001

Cited by 38 publications

(19 citation statements)

References 36 publications

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“…1). Free energy values have been widely used to estimate docking potential (Bak et al, 2013;Baker and Chandsawangbhuwana, 2012;Dolenc et al, 2011;Motto et al, 2011) and to develop Quantitative Structure Activity Relationship (QSAR) models (Li et al, 2011(Li et al, , 2010Yang et al, 2011). To validate the new AhR homology model, Motto et al (2011) compared free energies of binding predicted by the model with empirical values of pEC 50 and demonstrated good correlation (R 2 = 0.81).…”

Section: Comparison Between In Vitro Measurement and In Silico Modelingmentioning

confidence: 96%

“…Studies based on various structure-activity relationships, such as quantitative structure-activity relationship (QSAR) have been conducted for dioxin-like compounds (Ashek et al, 2006;Beger and Wilkes, 2001;Li et al, 2011;Yang et al, 2009). Approaches based on molecular docking have proven helpful in investigating detailed intermolecular interactions (Shin and Seok, 2012;Wang et al, 2013;Yuan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues

et al. 2015

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Section: Comparison Between In Vitro Measurement and In Silico Modelingmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues

et al. 2015

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“…Further study is needed to determine involvement of electrophilic modification of Hsp90 during quinones-mediated activation of AhR. Mouse AhR consisting of a basic region/helix-loophelix motif, Per-Arnt-Sim domain, and Q-rich domain, possesses 17 cysteine residues, including Cys327 corresponding to human Cys333 in the ligand binding pocket of AhR (Denison et al, 2002;Li et al, 2011). Mutation of Cys327 repressed TCDD-specific binding to AhR (Pandini et al, 2007), suggesting that arylation of Cys327 may be a factor for 1,2-NQ-mediated activation of AhR.…”

Section: Discussionmentioning

confidence: 99%

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

2015

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-Highly reactive quinone species produced by photooxidation and/or metabolic activation of mono-or bi-aromatic hydrocarbons modulate cellular homeostasis and electrophilic signal transduction pathways through the covalent modification of proteins. Polycyclic aromatic hydrocarbons, but not mono-or bi-aromatic hydrocarbons, are well recognized as ligands for the aryl hydrocarbon receptor (AhR). However, quinone species produced from mono-and bi-aromatic hydrocarbons could potentially cause AhR activation. To clarify the AhR response to mono-and bi-aromatic hydrocarbon quinones, we studied Cyp1a1 (cytochrome P450 1A1) induction and AhR activation by these quinones. We detected Cyp1a1 induction during treatment with quinones in Hepa1c1c7 cells, but not their parent compounds. Nine of the twelve quinones with covalent binding capability for proteins induced Cyp1a1. Cyp1a1 induction mediated by 1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone (1,4-BQ) and tert-butyl-1,4-BQ was suppressed by a specific AhR inhibitor and was not observed in c35 cells, which do not have a functional AhR. These quinones stimulated AhR nuclear translocation and interaction with the AhR nuclear translocator. Interestingly, 1,2-NQ covalently modified AhR, which was detected by an immunoprecipitation assay using a specific antibody against 1,2-NQ, resulting in enhancement of xenobiotic responsive element (XRE)-derived luciferase activity and binding of AhR to the Cyp1a1 promoter region. While mono-and bi-aromatic hydrocarbons are generally believed to be poor ligands for AhR and hence unable to induce Cyp1a1, our study suggests that the quinones of these molecules are able to modify AhR and activate the AhR/XRE pathway, thereby inducing Cyp1a1. Since we previously reported that 1,2-NQ and tert-butyl-1,4-BQ also activate NF-E2-related factor 2, it seems likely that some of quinones are bi-functional inducers for phase-I and phase-II reaction of xenobiotics.

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“…A range of QSAR models have been developed for predicting endocrine-related effects, such as binding to transport proteins such as transthyretin (Yang et al, 2011;Papa et al, 2013), and to various receptors including: progesterone (So et al, 2000;Chen et al, 2003;Soderholm et al, 2006;Pal et al, 2011), aryl hydrocarbon (Rayne et al, 2010;Li et al, 2011Li et al, , 2013bCao et al, 2013;Yuan et al, 2013), thyroid receptor (Liu and Gramatica, 2007;Valadares et al, 2007;Vedani et al, 2007;Du et al, 2008;Li et al, 2010Li et al, , 2012, and peroxisome proliferator-activated receptor (Devillers et al, 2006;Vedani et al, 2009). Many of these models can be applied only to a limited number of compounds.…”

Section: Introductionmentioning

confidence: 99%

Identifying potential endocrine disruptors among industrial chemicals and their metabolites – development and evaluation of in silico tools

et al. 2015

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The aim of this study was to improve the identification of endocrine disrupting chemicals (EDCs) by developing and evaluating in silico tools that predict interactions at the estrogen (E) and androgen (A) receptors, and binding to transthyretin (T). In particular, the study focuses on evaluating the use of the EAT models in combination with a metabolism simulator to study the significance of bioactivation for endocrine disruption. Balanced accuracies of the EAT models ranged from 77-87%, 62-77%, and 65-89% for E-, A-, and T-binding respectively. The developed models were applied on a set of more than 6000 commonly used industrial chemicals of which 9% were predicted E- and/or A-binders and 1% were predicted T-binders. The numbers of E- and T-binders increased 2- and 3-fold, respectively, after metabolic transformation, while the number of A-binders marginally changed. In-depth validation confirmed that several of the predicted bioactivated E- or T-binders demonstrated in vivo estrogenic activity or influenced blood levels of thyroxine in vivo. The metabolite simulator was evaluated using in vivo data from the literature which showed a 50% accuracy for studied chemicals. The study stresses, in summary, the importance of including metabolic activation in prioritization activities of potentially emerging contaminants.

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Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

Cited by 38 publications

References 36 publications

Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues

Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Identifying potential endocrine disruptors among industrial chemicals and their metabolites – development and evaluation of in silico tools

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