Three-Dimensional Proteome-Wide Scale Screening for the 5‑Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target

Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidis...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-04, Vol.64 (8), p.4553-4566
Main Authors: Giatti, Silvia, Di Domizio, Alessandro, Diviccaro, Silvia, Falvo, Eva, Caruso, Donatella, Contini, Alessandro, Melcangi, Roberto Cosimo
Format: Article
Language:English
Subjects:
5-alpha Reductase Inhibitors - chemistry
5-alpha Reductase Inhibitors - metabolism
5-alpha Reductase Inhibitors - pharmacology
Animals
Binding Sites
Binding, Competitive
Catecholamines - analysis
Catecholamines - metabolism
Chromatography, High Pressure Liquid
Databases, Protein
Epinephrine - metabolism
Finasteride - chemistry
Finasteride - metabolism
Finasteride - pharmacology
Humans
Male
Molecular Docking Simulation
Molecular Dynamics Simulation
Phenylethanolamine N-Methyltransferase - chemistry
Phenylethanolamine N-Methyltransferase - metabolism
Protein Binding
Rats
Rats, Sprague-Dawley
Tandem Mass Spectrometry
Thermodynamics
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Summary:Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by in vitro assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an in vivo rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.0c02039