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.