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J Steroid Biochem Mol Biol. 2019 Sep;192:105358. doi: 10.1016/j.jsbmb.2019.04.007. Epub 2019 Apr 6.

Identification of the fungicide epoxiconazole by virtual screening and biological assessment as inhibitor of human 11β-hydroxylase and aldosterone synthase.

Author information

1
Institute of Pharmacy / Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria; Department of Medicinal and Pharmaceutical Chemistry, Institute of Pharmacy, Paracelsus Medical University, Strubergasse 22, 5020, Salzburg, Austria. Electronic address: Muhammad.Akram@pmu.ac.at.
2
Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address: Melanie.Patt@unibas.ch.
3
Institute of Pharmacy / Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria. Electronic address: Teresa.Kaserer@uibk.ac.at.
4
Institute of Pharmacy / Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria. Electronic address: Veronika.Temml@uibk.ac.at.
5
Department of Chemistry, Faculty of Science and Technology, Rambhai Barni Rajabhat University, 22000, Chanthaburi, Thailand. Electronic address: Watcharee.W@rbru.ac.th.
6
Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address: Denise.Kratschmar@unibas.ch.
7
Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany. Electronic address: Joerg.Haupenthal@helmholtz-hips.de.
8
Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123, Saarbrücken, Germany. Electronic address: Rolf.Hartmann@helmholtz-hzi.de.
9
Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address: Alex.Odermatt@unibas.ch.
10
Institute of Pharmacy / Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria; Department of Medicinal and Pharmaceutical Chemistry, Institute of Pharmacy, Paracelsus Medical University, Strubergasse 22, 5020, Salzburg, Austria. Electronic address: Daniela.Schuster@uibk.ac.at.

Abstract

Humans are constantly exposed to a multitude of environmental chemicals that may disturb endocrine functions. It is crucial to identify such chemicals and uncover their mode-of-action to avoid adverse health effects. 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) catalyze the formation of cortisol and aldosterone, respectively, in the adrenal cortex. Disruption of their synthesis by exogenous chemicals can contribute to cardio-metabolic diseases, chronic kidney disease, osteoporosis, and immune-related disorders. This study applied in silico screening and in vitro evaluation for the discovery of xenobiotics inhibiting CYP11B1 and CYP11B2. Several databases comprising environmentally relevant pollutants, chemicals in body care products, food additives and drugs were virtually screened using CYP11B1 and CYP11B2 pharmacophore models. A first round of biological testing used hamster cells overexpressing human CYP11B1 or CYP11B2 to analyze 25 selected virtual hits. Three compounds inhibited CYP11B1 and CYP11B2 with IC50 values below 3 μM. The most potent inhibitor was epoxiconazole (IC50 value of 623 nM for CYP11B1 and 113 nM for CYP11B2, respectively); flurprimidol and ancymidol were moderate inhibitors. In a second round, these three compounds were tested in human adrenal H295R cells endogenously expressing CYP11B1 and CYP11B2, confirming the potent inhibition by epoxiconazole and the more moderate effects by flurprimidol and ancymidol. Thus, the in silico screening, prioritization of chemicals for initial biological tests and use of H295R cells to provide initial mechanistic information is a promising strategy to identify potential endocrine disruptors inhibiting corticosteroid synthesis. A critical assessment of human exposure levels and in vivo evaluation of potential corticosteroid disrupting effects by epoxiconazole is required.

KEYWORDS:

Aldosterone synthase; Cortisol synthase; Endocrine disruption; Environmental chemical; Fungicide; Pharmacophore modeling; Steroidogenesis; Virtual screening

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