5EN4

Complex of 17-beta-hydroxysteroid dehydrogenase type 14 with inhibitor.

Summary for 5EN4

• Entry DOI: 10.2210/pdb5en4/pdb
• Related: 1YDE
• Descriptor: 17-beta-hydroxysteroid dehydrogenase 14, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, [2,3-bis(oxidanyl)phenyl]-[6-(2-fluoranyl-3-oxidanyl-phenyl)pyridin-2-yl]methanone, ... (5 entities in total)
• Functional Keywords: inhibitor complex, steroid dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9BPX1
• Total number of polymer chains: 1
• Total formula weight: 29355.13

Authors

Bertoletti, N.,Braun, F.,Marchais-Oberwinkler, S.,Heine, A.,Klebe, G. (deposition date: 2015-11-09, release date: 2016-11-23, Last modification date: 2024-01-10)

Primary citation

Braun, F.,Bertoletti, N.,Moller, G.,Adamski, J.,Steinmetzer, T.,Salah, M.,Abdelsamie, A.S.,van Koppen, C.J.,Heine, A.,Klebe, G.,Marchais-Oberwinkler, S.
First Structure-Activity Relationship of 17 beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.
J. Med. Chem., 59:10719-10737, 2016

PubMed 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 K equal 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.

PubMed: 27933965
DOI: 10.1021/acs.jmedchem.6b01436

Experimental method

X-RAY DIFFRACTION (1.52 Å)