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PDBsum entry 4x6h
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References listed in PDB file
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Key reference
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Title
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Development of n-(Functionalized benzoyl)-Homocycloleucyl-Glycinonitriles as potent cathepsin k inhibitors.
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Authors
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J.Borišek,
M.Vizovišek,
P.Sosnowski,
B.Turk,
D.Turk,
B.Mohar,
M.Novič.
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Ref.
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J Med Chem, 2015,
58,
6928-6937.
[DOI no: ]
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PubMed id
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Abstract
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Cathepsin K is a major drug target for osteoporosis and related-bone disorders.
Using a combination of virtual combinatorial chemistry, QSAR modeling, and
molecular docking studies, a series of cathepsin K inhibitors based on
N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was
developed. In order to avoid previous problems of cathepsin K inhibitors
associated with lysosomotropism of compounds with basic character that resulted
in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3
position. Compounds 5, 6, and 9 were highly selective for cathepsin K when
compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The
kinetic studies revealed that the new compounds exhibited reversible tight
binding to cathepsin K, while the X-ray structural studies showed covalent and
noncovalent binding between the nitrile group and the catalytic cysteine (Cys25)
site.
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