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

Marie-Christin Jäger; Jacek Kędzierski; Victoria Gell; Tim Wey; Jakub Kollár; Denise V Winter; Daniela Schuster; Martin Smieško; Alex Odermatt

doi:10.1016/j.taap.2023.116638

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

Toxicol Appl Pharmacol. 2023 Sep 15:475:116638. doi: 10.1016/j.taap.2023.116638. Epub 2023 Jul 26.

Authors

Marie-Christin Jäger¹, Jacek Kędzierski², Victoria Gell³, Tim Wey⁴, Jakub Kollár⁵, Denise V Winter⁶, Daniela Schuster⁷, Martin Smieško⁸, Alex Odermatt⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: Tim.wey@protonmail.ch.
⁵ Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria. Electronic address: jakub.kollar@pmu.ac.at.
⁶ 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.
⁷ Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria. Electronic address: daniela.schuster@pmu.ac.at.
⁸ 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.
⁹ 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.

PMID: 37499767
DOI: 10.1016/j.taap.2023.116638

Abstract

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 IC₅₀ values in the nanomolar range. Inhibitors include retinoic acid metabolism blocking agents (RAMBAs), azole antifungals, α₂-adrenoceptor ligands, and a farnesyltransferase inhibitor. The active compounds share a nitrogen atom embedded in an aromatic ring system. Structure activity analysis identified the free electron pair of the nitrogen atom as a prerequisite for the drug-enzyme interaction, with its pK_a value as an indicator of inhibitory potency. Another important parameter is drug lipophilicity, exemplified by etomidate. Changing its ethyl ester moiety to a more hydrophilic carboxylic acid group dramatically decreased the inhibitory potential, most likely due to less efficient cellular uptake. The presented work successfully combined different in silico and in vitro methods to identify several previously unknown CYP11B1 inhibitors. This workflow facilitates the identification of compounds that inhibit CYP11B1 and therefore pose a risk for inducing hypertension and hypokalemia.

Keywords: CYP11B1; Hypertension; Off-Target Binding; Pharmacophore Modeling; Pseudohyperaldosteronism; Structure-Based Virtual Screening.

Publication types

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

MeSH terms

Humans
Hypertension* / chemically induced
Hypertension* / drug therapy
Hypokalemia* / complications
Steroid 11-beta-Hydroxylase / metabolism
Steroids

Substances

Steroid 11-beta-Hydroxylase
Steroids