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

• Published in: Toxicology and applied pharmacology 2023-09, Vol.475, p.116638-116638, Article 116638
• Main Authors: Jäger, Marie-Christin, Kędzierski, Jacek, Gell, Victoria, Wey, Tim, Kollár, Jakub, Winter, Denise V., Schuster, Daniela, Smieško, Martin, Odermatt, Alex
• Format: Article
• Language: English
• Subjects: CYP11B1; Hypertension; Off-Target Binding; Pharmacophore Modeling; Pseudohyperaldosteronism; Structure-Based Virtual Screening
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2023.116638

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 pKa 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. [Display omitted] •Virtual screening by ligand-based pharmacophores and induced fit docking facilitates identification of CYP11B1 inhibitors•Computational prediction combined with cell-free and cell-based activity assays identified potent CYP11B1 inhibitors•Identified CYP11B1 inhibitors include RAMBAs, azole antifungals, α2-adrenoceptor ligands and farnesyltransferase inhibitors•Unwanted CYP11B1 inhibition by drugs poses a risk for hypertension and hypokalemia