Open AccessLigand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors
Author(s) -
Anna Vuorinen,
Roger T. Engeli,
Arne Meyer,
Fabio Bachmann,
Ulrich J. Griesser,
Daniela Schuster,
Alex Odermatt
Publication year - 2014
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm5004914
Subject(s) - pharmacophore , virtual screening , chemistry , hydroxysteroid dehydrogenase , estrone , ligand (biochemistry) , enzyme , steroid , aromatase , drug discovery , hydroxysteroid dehydrogenases , in silico , ic50 , stereochemistry , dehydrogenase , structure–activity relationship , combinatorial chemistry , in vitro , biochemistry , receptor , medicine , cancer , breast cancer , hormone , gene
17β-Hydroxysteroid dehydrogenase 2 (17β-HSD2) catalyzes the inactivation of estradiol into estrone. This enzyme is expressed only in a few tissues, and therefore its inhibition is considered as a treatment option for osteoporosis to ameliorate estrogen deficiency. In this study, ligand-based pharmacophore models for 17β-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17β-HSD2 inhibition. Seven compounds inhibited 17β-HSD2 with low micromolar IC50 values. To investigate structure-activity relationships (SAR), 30 more derivatives of the original hits were tested. The three most potent hits, 12, 22, and 15, had IC50 values of 240 nM, 1 μM, and 1.5 μM, respectively. All but 1 of the 13 identified inhibitors were selective over 17β-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17β-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs.