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Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Vuorinen Anna, Engeli Roger T., Leugger Susanne, Bachmann Fabio, Akram Muhammad, Atanasov Atanas G., Waltenberger Birgit, Temml Veronika, Stuppner Hermann, Krenn Liselotte, Ateba Sylvin B., Njamen Dieudonné, Davis Rohan A., Odermatt Alex, Schuster Daniela,
Project Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation
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Original article (peer-reviewed)

Journal Journal of Natural Products
Volume (Issue) 80(4)
Page(s) 965 - 974
Title of proceedings Journal of Natural Products
DOI 10.1021/acs.jnatprod.6b00950

Open Access

Type of Open Access Publisher (Gold Open Access)


© 2017 The American Chemical Society and American Society of Pharmacognosy. 17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ 4 -androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC 50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC 50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC 50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC 50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC 50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure-activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.