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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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A carboxylic acid based inhibitor in complex with mmp3
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Structure:
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Stromelysin-1. Chain: a, b. Fragment: catalytic domain, residues 100-272. Synonym: mmp-3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Cell: fibroblast. Gene: mmp3. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.50Å
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R-factor:
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0.190
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R-free:
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0.220
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Authors:
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M.G.Natchus,R.G.Bookland,M.J.Laufersweiler,S.Pikul,N.G.Almst M.J.Janusz,L.C.Hsieh,F.Gu,M.E.Pokross,V.S.Patel,S.M.Garver, T.M.Branch,S.L.King,T.R.Baker,D.J.Foltz,G.E.Mieling
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Key ref:
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M.G.Natchus
et al.
(2001).
Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.
J Med Chem,
44,
1060-1071.
PubMed id:
DOI:
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Date:
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18-Jan-01
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Release date:
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18-Jan-02
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PROCHECK
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Headers
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References
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Enzyme class:
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Chains A, B:
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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Calcium; Zinc
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Gene Ontology (GO) functional annotation
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Cellular component
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extracellular matrix
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1 term
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Biological process
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proteolysis
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1 term
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Biochemical function
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metallopeptidase activity
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3 terms
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DOI no:
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J Med Chem
44:1060-1071
(2001)
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PubMed id:
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Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.
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M.G.Natchus,
R.G.Bookland,
M.J.Laufersweiler,
S.Pikul,
N.G.Almstead,
B.De,
M.J.Janusz,
L.C.Hsieh,
F.Gu,
M.E.Pokross,
V.S.Patel,
S.M.Garver,
S.X.Peng,
T.M.Branch,
S.L.King,
T.R.Baker,
D.J.Foltz,
G.E.Mieling.
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ABSTRACT
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A series of carboxylic acids were prepared from a propargylglycine scaffold and
tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR
for the series is reported for four enzymes within the MMP family. The
inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A
(MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited
stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a
compound with reasonable potency. Introduction of polar groups was required in
order to generate inhibitors with acceptable water solubility, and this often
resulted in a loss of potency as in compound 63. High serum protein binding
proved to be a difficult hurdle with many compounds such as 48 showing >99%
binding. Some compounds such as 64 displayed approximately 90% binding, but no
reliable method was discovered for designing molecules with low protein binding.
Finally, selected data regarding the pharmacokinetic behavior of these compounds
is presented.
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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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V.M.Baragi,
G.Becher,
A.M.Bendele,
R.Biesinger,
H.Bluhm,
J.Boer,
H.Deng,
R.Dodd,
M.Essers,
T.Feuerstein,
B.M.Gallagher,
C.Gege,
M.Hochgürtel,
M.Hofmann,
A.Jaworski,
L.Jin,
A.Kiely,
B.Korniski,
H.Kroth,
D.Nix,
B.Nolte,
D.Piecha,
T.S.Powers,
F.Richter,
M.Schneider,
C.Steeneck,
I.Sucholeiki,
A.Taveras,
A.Timmermann,
J.Van Veldhuizen,
J.Weik,
X.Wu,
and
B.Xia
(2009).
A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.
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Arthritis Rheum, 60,
2008-2018.
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M.Xue,
N.T.Le,
and
C.J.Jackson
(2006).
Targeting matrix metalloproteases to improve cutaneous wound healing.
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Expert Opin Ther Targets, 10,
143-155.
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S.Y.Huang,
and
X.Zou
(2006).
An iterative knowledge-based scoring function to predict protein-ligand interactions: II. Validation of the scoring function.
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J Comput Chem, 27,
1876-1882.
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J.Kaiser,
S.S.Kinderman,
B.C.van Esseveldt,
F.L.van Delft,
H.E.Schoemaker,
R.H.Blaauw,
and
F.P.Rutjes
(2005).
Synthetic applications of aliphatic unsaturated alpha-H-alpha-amino acids.
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Org Biomol Chem, 3,
3435-3467.
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Y.Hu,
J.S.Xiang,
M.J.DiGrandi,
X.Du,
M.Ipek,
L.M.Laakso,
J.Li,
W.Li,
T.S.Rush,
J.Schmid,
J.S.Skotnicki,
S.Tam,
J.R.Thomason,
Q.Wang,
and
J.I.Levin
(2005).
Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
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Bioorg Med Chem, 13,
6629-6644.
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M.A.Rudek,
J.Venitz,
and
W.D.Figg
(2002).
Matrix metalloproteinase inhibitors: do they have a place in anticancer therapy?
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Pharmacotherapy, 22,
705-720.
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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.
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Links
