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PDBsum entry 5o7c
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Oxidoreductase
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PDB id
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5o7c
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References listed in PDB file
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Key reference
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Title
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Structure-Based design and profiling of novel 17β-Hsd14 inhibitors.
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Authors
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F.Braun,
N.Bertoletti,
G.Möller,
J.Adamski,
M.Frotscher,
N.Guragossian,
P.A.Madeira gírio,
M.Le borgne,
L.Ettouati,
P.Falson,
S.Müller,
G.Vollmer,
A.Heine,
G.Klebe,
S.Marchais-Oberwinkler.
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Ref.
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Eur J Med Chem, 2018,
155,
61-76.
[DOI no: ]
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PubMed id
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Abstract
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The human enzyme 17β-hydroxysteroid dehydrogenase 14 (17β-HSD14) oxidizes the
hydroxyl group at position 17 of estradiol and 5-androstenediol using
NAD+ as cofactor. However, the physiological role of the enzyme
remains unclear. We recently described the first class of nonsteroidal
inhibitors for this enzyme with compound 1 showing a high 17β-HSD14 inhibitory
activity. Its crystal structure was used as starting point for a structure-based
optimization in this study. The goal was to develop a promising chemical probe
to further investigate the enzyme. The newly designed compounds revealed mostly
very high inhibition of the enzyme and for seven of them the crystal structures
of the corresponding inhibitor-enzyme complexes were resolved. The crystal
structures disclosed that a small change in the substitution pattern of the
compounds resulted in an alternative binding mode for one inhibitor. The
profiling of a set of the most potent inhibitors identified 13
(Ki = 9 nM) with a good selectivity profile toward three
17β-HSDs and the estrogen receptor alpha. This inhibitor displayed no
cytotoxicity, good solubility, and auspicious predicted bioavailability.
Overall, 13 is a highly interesting 17β-HSD14 inhibitor, which might be used as
chemical probe for further investigation of the target enzyme.
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