Ligand-based pharmacophore modeling and virtual screening for the discovery of novel 17?-hydroxysteroid dehydrogenase 2 inhibitors.

ABSTRACT: 17?-Hydroxysteroid dehydrogenase 2 (17?-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 17?-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17?-HSD2 inhibition. Seven compounds inhibited 17?-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 ?M, and 1.5 ?M, respectively. All but 1 of the 13 identified inhibitors were selective over 17?-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17?-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs.

SUBMITTER: Vuorinen A 

PROVIDER: S-EPMC4111740 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature