[en] 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.
Disciplines :
Environmental sciences & ecology
Author, co-author :
Goya-Jorge, Elizabeth ; Université de Liège - ULiège > Département de sciences des denrées alimentaires (DDA) > Gestion de la qualité dans la chaîne alimentaire
Giner, Rosa M; University of Valencia > Department of Pharmacology > Professor
Veitía, Maité Sylla-Iyarreta; Conservatoire National des Arts et Métiers (Cnam) > Equipe de Chimie Moléculaire du Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (EA 7528) > Professor
Gozalbes, Rafael; ProtoQSAR SL > PhD
Barigye, Stephen J; ProtoQSAR SL > PhD
Language :
English
Title :
Predictive modeling of aryl hydrocarbon receptor (AhR) agonism
H2020 - 722634 - PROTECTED - PROTECTion against Endocrine Disruptors; Detection, mixtures, health effects, risk assessment and communication.
Name of the research project :
PROTECTED - PROTECTion against Endocrine Disruptors; Detection, mixtures, health effects, risk assessment and communication
Funders :
CE - Commission Européenne [BE] Union Européenne [BE]
Funding number :
722634
Funding text :
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722634.
Barigye, S.J., Marrero-Ponce, Y., Digital communication and chemical structure codification. Meyers, R.A., (eds.) Encyclopedia of Complexity and Systems Science, 2016, Springer Berlin Heidelberg, Berlin, Heidelberg, 1–28, 10.1007/978-3-642-27737-5_625-2.
Bock, K.W., From TCDD-mediated toxicity to searches of physiologic AHR functions. Biochem. Pharmacol. 155 (2018), 419–424, 10.1016/j.bcp.2018.07.032.
Bradshaw, T., Westwell, A., The development of the antitumour benzothiazole prodrug, phortress, as a clinical candidate. Curr. Med. Chem. 11 (2005), 1009–1021, 10.2174/0929867043455530.
Chan, H.Y., Wang, H., Leung, L.K., The red clover (Trifolium pratense) isoflavone biochanin A modulates the biotransformation pathways of 7, 12-dimethylbenz[a]anthracene. Br. J. Nutr. 90 (2003), 87–92, 10.1079/BJN2003868.
Cherkasov, A., Muratov, E.N., Fourches, D., Varnek, A., Baskin, I.I., Cronin, M., Dearden, J., Gramatica, P., Martin, Y.C., Todeschini, R., Consonni, V., Kuz'Min, V.E., Cramer, R., Benigni, R., Yang, C., Rathman, J., Terfloth, L., Gasteiger, J., Richard, A., Tropsha, A., QSAR modeling: where have you been? Where are you going to?. J. Med. Chem. 57 (2014), 4977–5010, 10.1021/jm4004285.
Chitrala, K.N., Yang, X., Nagarkatti, P., Nagarkatti, M., Comparative analysis of interactions between aryl hydrocarbon receptor ligand binding domain with its ligands: a computational study. BMC Struct. Biol., 18, 2018, 10.1186/s12900-018-0095-2.
Ciolino, H.P., Daschner, P.J., Wang, T.T.Y., Yeh, G.C., Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells. Biochem. Pharmacol. 56 (1998), 197–206, 10.1016/S0006-2952(98)00143-9.
Esser, C., Lawrence, B.P., Sherr, D.H., Perdew, G.H., Puga, A., Barouki, R., Coumoul, X., Old receptor, new tricks—the ever-expanding universe of aryl hydrocarbon receptor functions. Report from the 4th AHR Meeting, 29–31 August 2018 in Paris, France. Int. J. Mol. Sci., vol. 19, 2018, 10.3390/ijms19113603.
Esser, C., Rannug, A., Stockinger, B., The aryl hydrocarbon receptor in immunity. Trends Immunol. 30 (2009), 447–454, 10.1016/j.it.2009.06.005.
Fujii-Kuriyama, Y., Mimura, J., Transcriptional roles of AhR in expression of biological effects induced by endocrine disruptors. Pure Appl. Chem. 75 (2007), 1819–1826, 10.1351/pac200375111819.
Gadaleta, D., Manganelli, S., Roncaglioni, A., Toma, C., Benfenati, E., Mombelli, E., QSAR modeling of ToxCast assays relevant to the molecular initiating events of AOPs leading to hepatic steatosis. J. Chem. Inf. Model. 58 (2018), 1501–1517, 10.1021/acs.jcim.8b00297.
Ghorbanzadeh, M., Van Ede, K.I., Larsson, M., Van Duursen, M.B.M., Poellinger, L., Lücke-Johansson, S., Machala, M., Pěnčíková, K., Vondráček, J., Van Den Berg, M., Denison, M.S., Ringsted, T., Andersson, P.L., In vitro and in silico derived relative effect potencies of ah-receptor-mediated effects by PCDD/Fs and PCBs in rat, mouse, and Guinea pig CALUX cell lines. Chem. Res. Toxicol. 27 (2014), 1120–1132, 10.1021/tx5001255.
Giani Tagliabue, S., Faber, S.C., Motta, S., Denison, M.S., Bonati, L., Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci. Rep. 9 (2019), 1–14, 10.1038/s41598-019-47138-z.
Gies, A., Neumeier, G., Rappolder, M., Konietzka, R., Risk assessment of dioxins and dioxin-like PCBs in food – comments by the German federal environmental agency. Chemosphere 67 (2007), S344–S349, 10.1016/j.chemosphere.2006.05.128.
Goya-Jorge, E., Doan, T.Q., Scippo, M.L., Muller, M., Giner, R.M., Barigye, S.J., Gozalbes, R., Elucidating the aryl hydrocarbon receptor antagonism from a chemical-structural perspective. SAR QSAR Environ. Res. 31 (2020), 209–226, 10.1080/1062936X.2019.1708460.
Guerrina, N., Traboulsi, H., Eidelman, D.H., Baglole, C.J., The aryl hydrocarbon receptor and the maintenance of lung health. Int. J. Mol. Sci., 19, 2018, 3882, 10.3390/ijms19123882.
Huang, R., Xia, M., Sakamuru, S., Zhao, J., Shahane, S.A., Attene-ramos, M., Zhao, T., Austin, C.P., Simeonov, A., Modelling the Tox21 10 K chemical profiles for in vivo toxicity prediction and mechanism characterization. Nat. Commun. 7 (2016), 1–10, 10.1038/ncomms10425.
Kawajiri, K., Fuji-Kuriyama, Y., The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. Exp. Anim. 66 (2016), 75–89, 10.1538/expanim.16-0092.
Klimenko, K., Rosenberg, S.A., Dybdahl, M., Wedebye, E.B., Nikolov, N.G., QSAR modelling of a large imbalanced aryl hydrocarbon activation dataset by rational and random sampling and screening of 80,086 REACH pre-registered and/or registered substances. PloS One 14 (2019), 1–21, 10.1371/journal.pone.0213848.
Mescher, M., Haarmann-Stemmann, T., Modulation of CYP1A1 metabolism: from adverse health effects to chemoprevention and therapeutic options. Pharmacol. Ther. 187 (2018), 71–87, 10.1016/j.pharmthera.2018.02.012.
Mitchell, K.A., Elferink, C.J., Timing is everything: consequences of transient and sustained AhR activity. Biochem. Pharmacol. 77 (2009), 947–956, 10.1016/j.bcp.2008.10.028.
Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65 (1983), 55–63, 10.1016/0022-1759(83)90303-4.
Nakai, R., Fukuda, S., Kawase, M., Yamashita, Y., Ashida, H., Curcumin and its derivatives inhibit 2,3,7,8,-tetrachloro-dibenzo-p-dioxin-induced expression of drug metabolizing enzymes through aryl hydrocarbon receptor-mediated pathway. Biosci. Biotechnol. Biochem. 82 (2017), 616–628, 10.1080/09168451.2017.1386086.
Nandekar, P.P., Sangamwar, A.T., Cytochrome P450 1A1-mediated anticancer drug discovery: in silico findings. Expet Opin. Drug Discov. 7 (2012), 771–789, 10.1517/17460441.2012.698260.
Nebert, D.W., Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals. Prog. Lipid Res. 67 (2017), 38–57, 10.1016/j.plipres.2017.06.001.
Nishiumi, S., Yoshida, K. ichi, Ashida, H., Curcumin suppresses the transformation of an aryl hydrocarbon receptor through its phosphorylation. Arch. Biochem. Biophys. 466 (2007), 267–273, 10.1016/j.abb.2007.08.007.
O'Donnell, E.F., Saili, K.S., Koch, D.C., Kopparapu, P.R., Farrer, D., Bisson, W.H., Mathew, L.K., Sengupta, S., Kerkvliet, N.I., Tanguay, R.L., Kolluri, S.K., The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PloS One, 5, 2010, 10.1371/journal.pone.0013128.
OECD. Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation in Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. 2016, 10.1787/9789264265295-en.
Puccetti, M., Paolicelli, G., Oikonomou, V., De Luca, A., Renga, G., Borghi, M., Pariano, M., Stincardini, C., Scaringi, L., Giovagnoli, S., Ricci, M., Romani, L., Zelante, T., Towards targeting the aryl hydrocarbon receptor in cystic fibrosis. Mediat. Inflamm., 2018, 1601486, 10.1155/2018/1601486 2018.
Roman, Á.C., Carvajal-Gonzalez, J.M., Merino, J.M., Mulero-Navarro, S., Fernández-Salguero, P.M., The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. Pharmacol. Ther. 185 (2018), 50–63, 10.1016/j.pharmthera.2017.12.003.
Rothhammer, V., Quintana, F.J., The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19 (2019), 184–197, 10.1038/s41577-019-0125-8.
Steinbeck, C., Han, Y., Kuhn, S., Horlacher, O., Luttmann, E., Willighagen, E., The Chemistry Development Kit (CDK): an open-source Java library for chemo- and bioinformatics. J. Chem. Inf. Comput. Sci. 43 (2003), 493–500, 10.1021/ci025584y.
Wang, Y., Cheng, T., Bryant, S.H., PubChem BioAssay: a decade's development toward open high-throughput screening data sharing. SLAS Discov 22 (2017), 655–666, 10.1177/2472555216685069.