PuSH - Publication Server of Helmholtz Zentrum München: First structure-activity relationship of 17<em>β</em>-hydroxysteroid dehydrogenase type 14 nonsteroidal inhibitors and crystal structures in complex with the enzyme.

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Braun, F.* ; Bertoletti, N.* ; Möller, 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 17β-hydroxysteroid dehydrogenase type 14 nonsteroidal inhibitors and crystal structures in complex with the enzyme.

J. Med. Chem. 59, 10719-10737 (2016)

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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 Ki 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.

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