title: First Structure-Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.
abstract: 17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Kiequal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed.
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Braun
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bertoletti
authors.affiliation: Genome Analysis Center, Institute of Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München , 85764 Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.affiliation: Genome Analysis Center, Institute of Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München , 85764 Neuherberg, Germany.|Chair of Experimental Genetics, Technical University Munich , 85350 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD) , 85764 Neuherberg, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.affiliation: ElexoPharm GmbH , Campus A1.2, 66123 Saarbrücken, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salah
authors.affiliation: ElexoPharm GmbH , Campus A1.2, 66123 Saarbrücken, Germany.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Abdelsamie
authors.affiliation: ElexoPharm GmbH , Campus A1.2, 66123 Saarbrücken, Germany.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: van Koppen
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase