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PDBsum entry 4mzs
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Hydrolase/hydrolase inhibitor
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PDB id
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4mzs
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References listed in PDB file
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Key reference
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Title
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Identification of potent and selective cathepsin s inhibitors containing different central cyclic scaffolds.
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Authors
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H.Hilpert,
H.Mauser,
R.Humm,
L.Anselm,
H.Kuehne,
G.Hartmann,
S.Gruener,
D.W.Banner,
J.Benz,
B.Gsell,
A.Kuglstatter,
M.Stihle,
R.Thoma,
R.A.Sanchez,
H.Iding,
B.Wirz,
W.Haap.
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Ref.
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J Med Chem, 2013,
56,
9789-9801.
[DOI no: ]
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PubMed id
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Abstract
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Starting from the weakly active dual CatS/K inhibitor 5, structure-based design
supported by X-ray analysis led to the discovery of the potent and selective
(>50 000-fold vs CatK) cyclopentane derivative 22 by exploiting specific
ligand-receptor interactions in the S2 pocket of CatS. Changing the central
cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the
enzyme as well as the cell-based activity significantly by 24- and 69-fold,
respectively. The most promising scaffold identified was the readily accessible
proline derivative (e.g., 79). This compound, with an appealing ligand
efficiency (LE) of 0.47, included additional structural modifications binding in
the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo
properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse
model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.
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