Virtual screening and biological evaluation to identify pharmaceuticals potentially causing hypertension and hypokalemia by inhibiting steroid 11β-hydroxylase.

Humans Hypertension / chemically induced Hypokalemia / complications Steroid 11-beta-Hydroxylase / metabolism Steroids
CYP11B1 Hypertension Off-Target Binding Pharmacophore Modeling Pseudohyperaldosteronism Structure-Based Virtual Screening

Journal

Toxicology and applied pharmacology
ISSN: 1096-0333
Titre abrégé: Toxicol Appl Pharmacol
Pays: United States
ID NLM: 0416575

Informations de publication

Date de publication:
15 09 2023
Historique:
received: 04 04 2023
revised: 21 07 2023
accepted: 24 07 2023
medline: 28 8 2023
pubmed: 28 7 2023
entrez: 27 7 2023
Statut: ppublish

Résumé

Several drugs were found after their market approval to unexpectedly inhibit adrenal 11β-hydroxylase (CYP11B1)-dependent cortisol synthesis. Known side-effects of CYP11B1 inhibition include hypertension and hypokalemia, due to a feedback activation of adrenal steroidogenesis, leading to supraphysiological concentrations of 11-deoxycortisol and 11-deoxycorticosterone that can activate the mineralocorticoid receptor. This results in potassium excretion and sodium and water retention, ultimately causing hypertension. With the risk known but usually not addressed in preclinical evaluation, this study aimed to identify drugs and drug candidates inhibiting CYP11B1. Two conceptually different virtual screening methods were combined, a pharmacophore based and an induced fit docking approach. Cell-free and cell-based CYP11B1 activity measurements revealed several inhibitors with IC

Identifiants

DOI: 10.1016/j.taap.2023.116638 PMID: 37499767
pubmed: 37499767
pii: S0041-008X(23)00277-6
doi: 10.1016/j.taap.2023.116638
pii:
doi:

Substances chimiques

Steroid 11-beta-Hydroxylase EC 1.14.15.4
Steroids 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

116638

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alex Odermatt reports financial support was provided by Swiss Centre for Applied Human Toxicology.

Auteurs

Marie-Christin Jäger (MC)

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: m.jaeger@unibas.ch.

Jacek Kędzierski (J)

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Division of Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland. Electronic address: jacek.kedzierski@unibas.ch.

Victoria Gell (V)

Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; Division of Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland. Electronic address: victoria.gell@cup.uni-muenchen.de.

Tim Wey (T)

Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: Tim.wey@protonmail.ch.

Jakub Kollár (J)

Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria. Electronic address: jakub.kollar@pmu.ac.at.

Denise V Winter (DV)

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: denise.winter@unibas.ch.

Daniela Schuster (D)

Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria. Electronic address: daniela.schuster@pmu.ac.at.

Martin Smieško (M)

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Division of Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland. Electronic address: martin.smiesko@unibas.ch.

Alex Odermatt (A)

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Virtual screening and biological evaluation to...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Hypertension artérielle › Virtual screening and biological evaluation to...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles de l'équilibre hydroélectrolytique › Hypokaliémie › Virtual screening and biological evaluation to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Steroid hydroxylases › Steroid 11-beta-hydroxylase › Virtual screening and biological evaluation to...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Virtual screening and biological evaluation to...