Demethoxylation of curcumin enhances its inhibition on human and rat 17β-hydroxysteroid dehydrogenase 3: QSAR structure-activity relationship and in silico docking analysis.

Ji, Z ; Sang, J ; et al.

In: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, Jg. 186 (2024-04-01), S. 114489

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Curcuminoids have many pharmacological effects. They or their metabolites may have side effects by suppressing 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3). Herein, we investigated the inhibition of curcuminoids and their metabolites on human and rat 17β-HSD3 and analyzed their structure-activity relationship (SAR) and performed in silico docking. Curcuminoids and their metabolites ranked in terms of IC 50 values against human 17β-HSD3 were bisdemethoxycurcumin (0.61 μM) > curcumin (8.63 μM) > demethoxycurcumin (9.59 μM) > tetrahydrocurcumin (22.04 μM) > cyclocurcumin (29.14 μM), and those against rat 17β-HSD3 were bisdemethoxycurcumin (3.94 μM) > demethoxycurcumin (4.98 μM) > curcumin (9.62 μM) > tetrahydrocurcumin (45.82 μM) > cyclocurcumin (143.5 μM). The aforementioned chemicals were mixed inhibitors for both enzymes. Molecular docking analysis revealed that they bind to the domain between the androstenedione and NADPH active sites of 17β-HSD3. Bivariate correlation analysis showed a positive correlation between LogP and pKa of curcumin derivatives with their IC 50 values. Additionally, a 3D-QSAR analysis revealed that a pharmacophore model consisting of three hydrogen bond acceptor regions and one hydrogen bond donor region provided a better fit for bisdemethoxycurcumin compared to curcumin. In conclusion, curcuminoids and their metabolites possess the ability to inhibit androgen biosynthesis by directly targeting human and rat 17β-HSD3. The inhibitory strength of these compounds is influenced by their lipophilicity and ionization characteristics.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Titel:	Demethoxylation of curcumin enhances its inhibition on human and rat 17β-hydroxysteroid dehydrogenase 3: QSAR structure-activity relationship and in silico docking analysis.
Autor/in / Beteiligte Person:	Ji, Z ; Sang, J ; Wang, H ; Xia, M ; Hao, T ; Chen, L ; Lu, H ; Wang, S ; Yao, M ; Li, L ; Ge, RS
Zeitschrift:	Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, Jg. 186 (2024-04-01), S. 114489
Veröffentlichung:	Exeter : Elsevier Science Ltd ; <i>Original Publication</i>: Oxford ; New York : Pergamon Press, c1982-, 2024
Medientyp:	academicJournal
ISSN:	1873-6351 (electronic)
DOI:	10.1016/j.fct.2024.114489
Schlagwort:	Humans Rats Animals Quantitative Structure-Activity Relationship Molecular Docking Simulation Structure-Activity Relationship Curcumin pharmacology Curcumin analogs & derivatives Pyrans 17-Hydroxysteroid Dehydrogenases Diarylheptanoids
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Food Chem Toxicol] 2024 Apr; Vol. 186, pp. 114489. <i>Date of Electronic Publication: </i>2024 Feb 13. MeSH Terms: Curcumin* / analogs & derivatives ; Curcumin / pharmacology ; Pyrans* ; 17-Hydroxysteroid Dehydrogenases* ; Diarylheptanoids* ; Humans ; Rats ; Animals ; Quantitative Structure-Activity Relationship ; Molecular Docking Simulation ; Structure-Activity Relationship Contributed Indexing: Keywords: 17β-HSD3; 17β-hydroxysteroid dehydrogenase 3; Curcuminoids; Molecular docking; Structure-activity relationship Substance Nomenclature: 0 (cyclocurcumin) ; 00U0645U03 (tetrahydrocurcumin) ; IT942ZTH98 (Curcumin) ; W2F8059T80 (demethoxycurcumin) ; EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase) ; 0 (Pyrans) ; EC 1.1.- (17-Hydroxysteroid Dehydrogenases) ; 0 (Diarylheptanoids) Entry Date(s): Date Created: 20240215 Date Completed: 20240329 Latest Revision: 20240329 Update Code: 20240329

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