|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
Chains A, B:
E.C.3.4.21.6
- coagulation factor Xa.
|
|
|
|
|
|
|
Reaction:
|
|
Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
J Med Chem
46:685-690
(2003)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Molecular structures of human factor Xa complexed with ketopiperazine inhibitors: preference for a neutral group in the S1 pocket.
|
|
S.Maignan,
J.P.Guilloteau,
Y.M.Choi-Sledeski,
M.R.Becker,
W.R.Ewing,
H.W.Pauls,
A.P.Spada,
V.Mikol.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The structures of the noncovalent complex of human factor Xa (fXa) with four
non-peptide inhibitors containing a central sulfonylpiperazinone scaffold have
been determined to about 2.1 A resolution. Highly potent fXa inhibitors
containing both neutral groups such as chlorobenzothiophene or chlorothiophene
and basic groups such as benzamidine were shown to interact in the S1 pocket
through the neutral group whereas the S4 pocket is occupied by the basic moiety.
The scaffold comprising the sulfonyl keto piperazine moiety might play a pivotal
role in the orientation of substituents, since there is a strong hydrogen bond
between Gly219 of fXa and the carbonyl oxygen of the piperazine. This unique
"reverse" binding mode is heretofore unreported in fXa and shows that
electrostatic interactions in the S1 subsite are not an absolute requirement to
maintain high affinity. Selectivity against other serine proteases can be
readily explained in light of these structural results. It has opened up new
prospects for designing fXa inhibitors with increased oral bioavailability.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
E.Perzborn,
S.Roehrig,
A.Straub,
D.Kubitza,
and
F.Misselwitz
(2011).
The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor.
|
| |
Nat Rev Drug Discov,
10,
61-75.
|
|
|
|
|
|
|
Y.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
|
| |
Med Res Rev,
31,
202-283.
|
|
|
|
|
|
|
H.G.Wallnoefer,
T.Fox,
K.R.Liedl,
and
C.S.Tautermann
(2010).
Dispersion dominated halogen-π interactions: energies and locations of minima.
|
| |
Phys Chem Chem Phys,
12,
14941-14949.
|
|
|
|
|
|
|
F.Quintus,
O.Sperandio,
J.Grynberg,
M.Petitjean,
and
P.Tuffery
(2009).
Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity.
|
| |
BMC Bioinformatics,
10,
245.
|
|
|
|
|
|
|
M.Limbach,
A.V.Lygin,
V.S.Korotkov,
M.Es-Sayed,
and
A.de Meijere
(2009).
Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as dipeptide mimics and templates.
|
| |
Org Biomol Chem,
7,
3338-3342.
|
|
|
|
|
|
|
C.Krishnasamy,
A.Raghuraman,
L.B.Kier,
and
U.R.Desai
(2008).
Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of pyrazole derivatives as inhibitors of factor xa and thrombin.
|
| |
Chem Biodivers,
5,
2609-2620.
|
|
|
|
|
|
|
N.Singh,
and
J.M.Briggs
(2008).
Molecular dynamics simulations of Factor Xa: insight into conformational transition of its binding subsites.
|
| |
Biopolymers,
89,
1104-1113.
|
|
|
|
|
|
|
R.Abel,
T.Young,
R.Farid,
B.J.Berne,
and
R.A.Friesner
(2008).
Role of the active-site solvent in the thermodynamics of factor Xa ligand binding.
|
| |
J Am Chem Soc,
130,
2817-2831.
|
|
|
|
|
|
|
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.
|
| |
Bioorg Med Chem,
16,
2243-2260.
|
|
|
|
|
|
|
Y.N.Imai,
Y.Inoue,
I.Nakanishi,
and
K.Kitaura
(2008).
Cl-pi interactions in protein-ligand complexes.
|
| |
Protein Sci,
17,
1129-1137.
|
|
|
|
|
|
|
C.A.Van Huis,
C.F.Bigge,
A.Casimiro-Garcia,
W.L.Cody,
D.A.Dudley,
K.J.Filipski,
R.J.Heemstra,
J.T.Kohrt,
L.S.Narasimhan,
R.P.Schaum,
E.Zhang,
J.W.Bryant,
S.Haarer,
N.Janiczek,
R.J.Leadley,
T.McClanahan,
J.Thomas Peterson,
K.M.Welch,
and
J.J.Edmunds
(2007).
Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
|
| |
Chem Biol Drug Des,
69,
444-450.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
J.T.Kohrt,
C.F.Bigge,
J.W.Bryant,
A.Casimiro-Garcia,
L.Chi,
W.L.Cody,
T.Dahring,
D.A.Dudley,
K.J.Filipski,
S.Haarer,
R.Heemstra,
N.Janiczek,
L.Narasimhan,
T.McClanahan,
J.T.Peterson,
V.Sahasrabudhe,
R.Schaum,
C.A.Van Huis,
K.M.Welch,
E.Zhang,
R.J.Leadley,
and
J.J.Edmunds
(2007).
The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.
|
| |
Chem Biol Drug Des,
70,
100-112.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
R.Fasan,
R.L.Dias,
K.Moehle,
O.Zerbe,
D.Obrecht,
P.R.Mittl,
M.G.Grütter,
and
J.A.Robinson
(2006).
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
|
| |
Chembiochem,
7,
515-526.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
K.Schärer,
M.Morgenthaler,
R.Paulini,
U.Obst-Sander,
D.W.Banner,
D.Schlatter,
J.Benz,
M.Stihle,
and
F.Diederich
(2005).
Quantification of cation-pi interactions in protein-ligand complexes: crystal-structure analysis of Factor Xa bound to a quaternary ammonium ion ligand.
|
| |
Angew Chem Int Ed Engl,
44,
4400-4404.
|
|
|
PDB code:
|
|
|
|
|
|
|
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
code is
shown on the right.
|
 |
Links
