Identification of chemically diverse, novel inhibitors of 17?-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening

17?-Hydroxysteroid dehydrogenase type 3 and 5 (17?-HSD3 and 17?-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17?HSD3/5, ligand- and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17?-HSD3 and 17?-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors.