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PDBsum entry 1nms
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Apoptosis, hydrolase
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PDB id
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1nms
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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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In situ assembly of enzyme inhibitors using extended tethering.
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Authors
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D.A.Erlanson,
J.W.Lam,
C.Wiesmann,
T.N.Luong,
R.L.Simmons,
W.L.Delano,
I.C.Choong,
M.T.Burdett,
W.M.Flanagan,
D.Lee,
E.M.Gordon,
T.O'Brien.
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Ref.
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Nat Biotechnol, 2003,
21,
308-314.
[DOI no: ]
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PubMed id
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Abstract
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Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a
therapeutic target for a wide range of diseases. Using a dynamic combinatorial
technology, 'extended tethering', we identified unique nonpeptidic inhibitors
for this enzyme. Extended tethering allowed the identification of ligands that
bind to discrete regions of caspase-3 and also helped direct the assembly of
these ligands into small-molecule inhibitors. We first designed a small-molecule
'extender' that irreversibly alkylates the cysteine residue of caspase-3 and
also contains a thiol group. The modified protein was then screened against a
library of disulfide-containing small-molecule fragments. Mass-spectrometry was
used to identify ligands that bind noncovalently to the protein and that also
form a disulfide linkage with the extender. Linking the selected fragments with
binding elements from the extenders generates reversible, tight-binding
molecules that are druglike and distinct from known inhibitors. One molecule
derived from this approach inhibited apoptosis in cells.
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Figure 1.
Figure 1. Schematic illustration of the extended tethering
technique.
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Figure 4.
Figure 4. Evolution of selected fragments into reversible
inhibitors of caspase-3. (A) SAR of the reversible (aldehyde)
inhibitors derived from the selected fragments shown in Figure
2A. (B) Superposition of caspase-3 modified with extender A and
the salicylic acid sulfonamide tethering hit (fragment A; gray)
and caspase-3 bound to an irreversible version (in which the
aldehyde was replaced with an arylacyloxymethyl ketone) of
compound 4 (salmon). The arrow indicates a minor structural
accommodation observed in the S4 region between the tether and
the rigidified inhibitor.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Biotechnol
(2003,
21,
308-314)
copyright 2003.
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Secondary reference #1
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Title
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Identification of potent and selective small-Molecule inhibitors of caspase-3 through the use of extended tethering and structure-Based drug design.
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Authors
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I.C.Choong,
W.Lew,
D.Lee,
P.Pham,
M.T.Burdett,
J.W.Lam,
C.Wiesmann,
T.N.Luong,
B.Fahr,
W.L.Delano,
R.S.Mcdowell,
D.A.Allen,
D.A.Erlanson,
E.M.Gordon,
T.O'Brien.
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Ref.
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J Med Chem, 2002,
45,
5005-5022.
[DOI no: ]
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PubMed id
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