Abstract
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-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 IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 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.
Highlights
Reductase (SDR) enzymes with the systematic name SDR9C2.1 It is mainly expressed in the placenta, endometrium, breast, prostate, small intestine, liver, and bone.[2−5] This NAD+
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
Owing to its favorable localization and its role as a main contributor to the inactivation of estradiol, testosterone, and 5α-dihydrotestosterone in bone cells,2 17β-HSD2 has been proposed as a promising target for the treatment of osteoporosis.[12]
Summary
Engeli,†,# Susanne Leugger,† Fabio Bachmann,† Muhammad Akram,‡ Atanas G. Atanasov,§,⊥ Birgit Waltenberger,∥ Veronika Temml,∥ Hermann Stuppner,∥ Liselotte Krenn,§ Sylvin B.
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