title: Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening.
abstract: 17β-Hydroxysteroid dehydrogenase type 3 and 5 (17β-HSD3 and 17β-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 17βHSD3/5, 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 17β-HSD3 and 17β-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors.
authors.affiliation: Computer-Aided Molecular Design Group and Center for Molecular Biosciences Innsbruck, Institute of Pharmacy/Pharmaceutical Chemistry, Innrain 52c, A-6020 Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Dorota
authors.initials: D
authors.lastname: Kowalik
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Christel
authors.initials: C
authors.lastname: Aebischer-Gumy
authors.forename: Fabian
authors.initials: F
authors.lastname: Ströhle
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Thomas
authors.initials: T
authors.lastname: Wilckens
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3