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
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Department of Pharmacognosy, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.
J Nat Prod. 2017 Apr 28;80(4):965-974. doi: 10.1021/acs.jnatprod.6b00950. Epub 2017 Mar 20.
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ-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 values. The most potent compounds, nordihydroguaiaretic acid (1), IC 0.38 ± 0.04 μM, (-)-dihydroguaiaretic acid (4), IC 0.94 ± 0.02 μM, isoliquiritigenin (6), IC 0.36 ± 0.08 μM, and ethyl vanillate (12), IC 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.
2型17β-羟基类固醇脱氢酶（17β-HSD2）分别将活性甾体激素雌二醇、睾酮和5α-二氢睾酮转化为活性较弱的形式——雌酮、Δ-雄烯-3,17-二酮和5α-雄烷-3,17-二酮，从而调节细胞和组织特异性甾体作用。由于活性甾体水平降低与骨骼健康受损和骨质疏松症的发生有关，17β-HSD2被认为是抗骨质疏松治疗的靶点。在本研究中，基于17β-HSD2抑制剂的药效团模型被应用于对包含天然产物的各种数据库进行虚拟筛选，以便从自然界中发现新的先导结构。总共选择了36个命中分子进行生物学评估。在这些化合物中，有12种以纳摩尔到低微摩尔的IC值抑制17β-HSD2。最有效的化合物，去甲二氢愈创木酸（1），IC为0.38±0.04μM，（-）-二氢愈创木酸（4），IC为0.94±0.02μM，异甘草素（6），IC为0.36±0.08μM，以及香草酸乙酯（12），IC为1.28±0.26μM，对17β-HSD1的选择性比其高8倍或更高。由于一些鉴定出的化合物属于同一结构类别，因此得出了这些分子的构效关系。因此，本研究描述了来自自然界的新型17β-HSD2抑制剂，并深入了解了17β-HSD2的结合口袋，为该领域的进一步研究提供了一个有前景的起点。
