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Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105

Author(s):

Preyesh Stephen, Jenny Roy, René Maltais and Donald Poirier*   Pages 1 - 8 ( 8 )

Abstract:


Background: The last step in the production of androgen testosterone from 4-androstene-3,17-dione (4-dione) in testis involves the 17-hydroxysteroid dehydrogenase type 3 (17-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known.

Objective: To identify potential binding sites of 17β-HSD3 substrate (4-dione), cofactor NADPH as well as inhibitor RM- 532-105.

Methods: Since there is no crystal structure of 17β-HSD3, complexed or not with a ligand, a homology model of this enzyme, molecular docking experiments and enzymatic assays were used.

Results: Molecular modeling experiments and enzymatic assays with transfected LNCaP prostate cancer cells, as source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in presence of varying concentrations of substrate, cofactor and inhibitor, suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione.

Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships

Keywords:

Enzyme inhibitor, 17beta-HSD3, steroid, androgen, docking

Affiliation:

Endocrinology and Nephrology Unit, CHU de Québec – Research Center, Québec, QC, Canada, Endocrinology and Nephrology Unit, CHU de Québec – Research Center, Québec, QC, Canada, Endocrinology and Nephrology Unit, CHU de Québec – Research Center, Québec, QC, Canada, Endocrinology and Nephrology Unit, CHU de Québec – Research Center, Québec, QC, Canada



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