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PDBsum entry 4y76
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PDB id:
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Hydrolase
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Title:
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Factor xa complex with gtc000401
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Structure:
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Coagulation factor x. Chain: a. Synonym: stuart factor,stuart-prower factor, activated factor xa heavy chain. Coagulation factor x. Chain: b. Fragment: unp residues 46-179. Synonym: stuart factor,stuart-prower factor, factor x light chain. Ec: 3.4.21.6
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606
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Resolution:
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2.00Å
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R-factor:
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0.190
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R-free:
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0.236
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Authors:
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M.A.Convery,R.J.Young,S.Senger,J.N.Hamblin,C.Chan,J.R.Toomey, N.S.Watson
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Key ref:
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C.Chan
et al.
(2007).
Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.
J Med Chem,
50,
1546-1557.
PubMed id:
DOI:
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Date:
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13-Feb-15
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Release date:
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30-Sep-15
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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.3.4.21.6
- coagulation factor Xa.
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Reaction:
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Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
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DOI no:
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J Med Chem
50:1546-1557
(2007)
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PubMed id:
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Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.
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C.Chan,
A.D.Borthwick,
D.Brown,
C.L.Burns-Kurtis,
M.Campbell,
L.Chaudry,
C.W.Chung,
M.A.Convery,
J.N.Hamblin,
L.Johnstone,
H.A.Kelly,
S.Kleanthous,
A.Patikis,
C.Patel,
A.J.Pateman,
S.Senger,
G.P.Shah,
J.R.Toomey,
N.S.Watson,
H.E.Weston,
C.Whitworth,
R.J.Young,
P.Zhou.
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ABSTRACT
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Factor Xa inhibitory activities for a series of
N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides
with different P1 groups are described. These data provide insight into binding
interactions within the S1 primary specificity pocket; rationales are presented
for the derived SAR on the basis of electronic interactions through crystal
structures of fXa-ligand complexes and molecular modeling studies. A good
correlation between in vitro anticoagulant activities with lipophilicity and the
extent of human serum albumin binding is observed within this series of potent
fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with
selectivity over other trypsin-like serine proteases, identified 1f as a
candidate for further evaluation.
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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.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
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Med Res Rev,
31,
202-283.
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H.G.Wallnoefer,
T.Fox,
K.R.Liedl,
and
C.S.Tautermann
(2010).
Dispersion dominated halogen-π interactions: energies and locations of minima.
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Phys Chem Chem Phys,
12,
14941-14949.
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M.A.Abboud,
S.J.Needle,
C.L.Burns-Kurtis,
R.E.Valocik,
P.F.Koster,
A.J.Amour,
C.Chan,
D.Brown,
L.Chaudry,
P.Zhou,
A.Patikis,
C.Patel,
A.J.Pateman,
R.J.Young,
N.S.Watson,
and
J.R.Toomey
(2008).
Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor.
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J Cardiovasc Pharmacol,
52,
66-71.
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Y.Imaeda,
T.Miyawaki,
H.Sakamoto,
F.Itoh,
N.Konishi,
K.Hiroe,
M.Kawamura,
T.Tanaka,
and
K.Kubo
(2008).
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors.
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Bioorg Med Chem,
16,
2243-2260.
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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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