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PDBsum entry 1d7x
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.17
- stromelysin 1.
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Reaction:
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Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
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Cofactor:
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Ca(2+); Zn(2+)
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DOI no:
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J Med Chem
42:5426-5436
(1999)
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PubMed id:
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Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.
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M.Cheng,
B.De,
N.G.Almstead,
S.Pikul,
M.E.Dowty,
C.R.Dietsch,
C.M.Dunaway,
F.Gu,
L.C.Hsieh,
M.J.Janusz,
Y.O.Taiwo,
M.G.Natchus,
T.Hudlicky,
M.Mandel.
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ABSTRACT
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The synthesis and structure-activity relationship (SAR) studies of a series of
proline-based matrix metalloproteinase inhibitors are described. The data reveal
a remarkable potency enhancement in those compounds that contain an sp(2) center
at the C-4 carbon of the ring relative to similar, saturated compounds. This
effect was noted in compounds that contained a functionalized oxime moiety or an
exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and
<100 nM for MMP-1. Comparisons were then made against compounds with similar
functionality where the C-4 carbon was reduced to sp(3) hybridization and the
effect was typically an order of magnitude loss in potency. A comparison of
compounds 14 and 34 exemplifies this observation. An X-ray structure was
obtained for a stromelysin-inhibitor complex which provided insights into the
SAR and selectivity trends observed within the series. In vitro intestinal
permeability data for many compounds was also accumulated.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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Y.Arakawa,
N.Yagi,
Y.Arakawa,
K.Tanaka,
and
S.Yoshifuji
(2009).
Conversion of 4-oxoproline esters to 4-substituted pyrrole-2-carboxylic acid esters.
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Chem Pharm Bull (Tokyo),
57,
167-176.
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L.A.Alcaraz,
L.Banci,
I.Bertini,
F.Cantini,
A.Donaire,
and
L.Gonnelli
(2007).
Matrix metalloproteinase-inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors.
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J Biol Inorg Chem,
12,
1197-1206.
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PDB codes:
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P.Conti,
G.Grazioso,
S.J.di Ventimiglia,
A.Pinto,
G.Roda,
U.Madsen,
H.Bräuner-Osborne,
B.Nielsen,
C.Costagli,
and
A.Galli
(2005).
Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors.
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Chem Biodivers,
2,
748-757.
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A.Scozzafava,
M.A.Ilies,
G.Manole,
and
C.T.Supuran
(2000).
Protease inhibitors. Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties.
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Eur J Pharm Sci,
11,
69-79.
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P.J.Gane,
and
P.M.Dean
(2000).
Recent advances in structure-based rational drug design.
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Curr Opin Struct Biol,
10,
401-404.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
