Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2.
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 IC50values. The most potent compounds, nordihydroguaiaretic acid (1), IC500.38 ± 0.04 μM, (-)-dihydroguaiaretic acid (4), IC500.94 ± 0.02 μM, isoliquiritigenin (6), IC500.36 ± 0.08 μM, and ethyl vanillate (12), IC501.28 ± 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.
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Anna
A
Vuorinen
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Roger T
RT
Engeli
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Susanne
S
Leugger
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Fabio
F
Bachmann
Muhammad
M
Akram
Department of Pharmacognosy, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.|Institute of Genetics and Animal Breeding of the Polish Academy of Sciences , Postępu 36A Street, 05-552, Jastrzebiec, Poland.
Atanas G
AG
Atanasov
Birgit
B
Waltenberger
Veronika
V
Temml
Hermann
H
Stuppner
Department of Pharmacognosy, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.
Liselotte
L
Krenn
Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I , P.O. Box 812, Yaounde, Cameroon.
Sylvin B
SB
Ateba
Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I , P.O. Box 812, Yaounde, Cameroon.
Dieudonné
D
Njamen
Griffith Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
Rohan A
RA
Davis
Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.
Alex
A
Odermatt
Daniela
0000-0002-9933-8938
D
Schuster
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005043:Etiocholanolone / Q000031:analogs & derivatives; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
D001688:Biological Products; D004791:Enzyme Inhibitors; D013739:Testosterone; C006576:androstane-3,17-dione; D005043:Etiocholanolone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase