Download MendeleyFirst Structure-Activity Relationship of 17 beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.
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.(2016) J Med Chem 59: 10719-10737
- PubMed: 27933965
- DOI: https://doi.org/10.1021/acs.jmedchem.6b01436
- Primary Citation of Related Structures:
5EN4, 5L7T, 5L7W, 5L7Y - 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 i 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.
Organizational Affiliation:
Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
