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PDBsum entry 1kyn
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Nonpeptide inhibitors of cathepsin g: optimization of a novel beta-Ketophosphonic acid lead by structure-Based drug design.
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Authors
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M.N.Greco,
M.J.Hawkins,
E.T.Powell,
H.R.Almond,
T.W.Corcoran,
L.De garavilla,
J.A.Kauffman,
R.Recacha,
D.Chattopadhyay,
P.Andrade-Gordon,
B.E.Maryanoff.
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Ref.
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J Am Chem Soc, 2002,
124,
3810-3811.
[DOI no: ]
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PubMed id
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Abstract
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The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the
azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released
on degranulation, has been implicated in various pathological conditions
associated with inflammation. By employing high-throughput screening, we
identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) =
4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve
its structure by X-ray crystallography (3.5 A). Structural details from the
X-ray analysis of 1.Cat G served as a platform for optimization of this lead
compound by structure-based drug design. With the aid of molecular modeling,
substituents were attached to the 3-position of the 2-naphthyl ring of 1, which
occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3
region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over
1 (IC(50) = 53 nM). From these results, it is evident that the
beta-ketophosphonic acid unit can form the basis for a novel class of serine
protease inhibitors.
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