 |
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase
|
|
|
Title:
|
|
A carboxylic acid based inhibitor in complex with mmp3
|
|
Structure:
|
|
Matrix metalloproteinase 3. Chain: a, b. Fragment: catalytic domain. Synonym: stromelysin 1, mmp3, progelatinase, transin-1, sl- 1. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Cell: fibroblast. Gene: mmp3. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
1.90Å
|
R-factor:
|
0.196
|
R-free:
|
0.253
|
|
|
Authors:
|
|
M.G.Natchus,R.G.Bookland,B.De,N.G.Almstead,S.Pikul
|
|
Key ref:
|
|
M.G.Natchus
et al.
(2000).
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.
J Med Chem,
43,
4948-4963.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
26-Oct-00
|
Release date:
|
24-Oct-01
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
|
|
|
|
P08254
(MMP3_HUMAN) -
Stromelysin-1
|
|
|
|
Seq:
Struc:
|
|
|
|
477 a.a.
169 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.3.4.24.17
- Stromelysin 1.
|
|
|
|
|
|
|
Reaction:
|
|
Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
|
|
|
|
|
|
Cofactor:
|
|
Calcium; Zinc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Gene Ontology (GO) functional annotation
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cellular component
|
extracellular matrix
|
1 term
|
|
|
Biological process
|
proteolysis
|
1 term
|
|
|
Biochemical function
|
metallopeptidase activity
|
3 terms
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
J Med Chem
43:4948-4963
(2000)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.
|
|
M.G.Natchus,
R.G.Bookland,
B.De,
N.G.Almstead,
S.Pikul,
M.J.Janusz,
S.A.Heitmeyer,
E.B.Hookfin,
L.C.Hsieh,
M.E.Dowty,
C.R.Dietsch,
V.S.Patel,
S.M.Garver,
F.Gu,
M.E.Pokross,
G.E.Mieling,
T.R.Baker,
D.J.Foltz,
S.X.Peng,
D.M.Bornes,
M.J.Strojnowski,
Y.O.Taiwo.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
A series of hydroxamates was prepared from an aminoproline scaffold and tested
for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the
series is reported for five enzymes within the MMP family, and a number of
inhibitors, such as compound 47, display broad-spectrum activity with
sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the
molecule played a key role in affecting both potency and selectivity within the
MMP family. Longer-chain aliphatic substituents in this region of the molecule
tended to increase potency for MMP-3 and decrease potency for MMP-1, as
exemplified by compounds 48-50, while aromatic substituents, as in compound 52,
generated broad-spectrum inhibition. The data is rationalized based upon X-ray
crystal data which is also presented. While the in vitro peroral absorption
seemed to be less predictable, it tended to decrease with longer and more
hydrophilic substituents. Finally, a rat model of osteoarthritis was used to
evaluate the efficacy of these compounds, and a direct link was established
between their pharmacokinetics and their in vivo efficacy.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
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.
|
| |
Arthritis Rheum, 60,
2008-2018.
|
|
|
|
|
|
|
M.Kontoyianni,
G.S.Sokol,
and
L.M.McClellan
(2005).
Evaluation of library ranking efficacy in virtual screening.
|
| |
J Comput Chem, 26,
11-22.
|
|
|
|
|
|
|
S.R.Wallner,
B.M.Nestl,
and
K.Faber
(2005).
Highly enantioselective stereo-inverting sec-alkylsulfatase activity of hyperthermophilic Archaea.
|
| |
Org Biomol Chem, 3,
2652-2656.
|
|
|
|
|
|
|
V.Lukacova,
Y.Zhang,
M.Mackov,
P.Baricic,
S.Raha,
J.A.Calvo,
and
S.Balaz
(2004).
Similarity of binding sites of human matrix metalloproteinases.
|
| |
J Biol Chem, 279,
14194-14200.
|
|
|
|
|
|
|
S.Wei,
Y.Chen,
L.Chung,
H.Nagase,
and
K.Brew
(2003).
Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors.
|
| |
J Biol Chem, 278,
9831-9834.
|
|
|
|
|
|
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.
|
|
Links
