In silico and in vitro assessment of drugs potentially causing adverse effects by inhibiting CYP17A1

  • Toxicol Appl Pharmacol. 2024 May:486:116945. doi: 10.1016/j.taap.2024.116945.
Jacek Kędzierski  1 ,  Marie-Christin Jäger  2 ,  Sadaf Naeem  3 ,  Alex Odermatt  4 ,  Martin Smieško  5
Affiliations
  • 1. Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Centre for Human Applied Toxicology, University of Basel, Missionsstrasse 64, Basel 4055, Switzerland. Electronic address: [email protected].
  • 2. Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Centre for Human Applied Toxicology, University of Basel, Missionsstrasse 64, Basel 4055, Switzerland. Electronic address: [email protected].
  • 3. Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Department of Biochemistry, University of Karachi, KU, Circular Road, Karachi, Pakistan.
  • 4. Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Centre for Human Applied Toxicology, University of Basel, Missionsstrasse 64, Basel 4055, Switzerland. Electronic address: [email protected].
  • 5. Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Centre for Human Applied Toxicology, University of Basel, Missionsstrasse 64, Basel 4055, Switzerland. Electronic address: [email protected].
PMID: 38688424 DOI: 10.1016/j.taap.2024.116945
Abstract

Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP Enzymes are frequently investigated as anti-targets, the inhibition of CYP Enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive Mineralocorticoid Receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate Cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate Cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.

Keywords
CYP17A1; Hypertension; Hypokalemia; Inhibitor; Pseudohyperaldosteronism; Virtual screening; Xenobiotic.
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