Finasteride, a 5-alpha reductase (5alpha-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 5alpha-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.

Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target / S. Giatti, A. Di Domizio, S. Diviccaro, E. Falvo, D. Caruso, A. Contini, C. Melcangi. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 64(2021 Apr 12), pp. 4553-4566. [10.1021/acs.jmedchem.0c02039]

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

S. Giatti
Co-primo
;
S. Diviccaro
Secondo
;
E. Falvo;D. Caruso;A. Contini
Penultimo
;
C. Melcangi
Ultimo
2021

Abstract

Finasteride, a 5-alpha reductase (5alpha-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 5alpha-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.
Finasteride, 5alpha-reductase, off-target, sexual dysfunction, hPNMT, molecular modeling
Settore MED/13 - Endocrinologia
Settore BIO/10 - Biochimica
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/02 - Chimica Fisica
Dipartimenti di Eccellenza 2018-2022 - Dipartimento di SCIENZE FARMACOLOGICHE E BIOMOLECOLARI
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/835389
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