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* Residue conservation analysis
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PDB id:
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Hydrolase/hyrolase inhibitor
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Title:
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Crystallographic analysis at 3.0-angstroms resolution of the binding to human thrombin of four active site-directed inhibitors
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Structure:
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Alpha-thrombin (small subunit). Chain: l. Engineered: yes. Alpha-thrombin (large subunit). Chain: h. Engineered: yes. Hirudin iiia. Chain: i. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organ: plasma. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
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Biol. unit:
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Trimer (from
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Resolution:
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Authors:
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D.W.Banner,P.Hadvary
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Key ref:
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D.W.Banner
and
P.Hadváry
(1991).
Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors.
J Biol Chem,
266,
20085-20093.
PubMed id:
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Date:
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19-Aug-92
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Release date:
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31-Jan-94
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PROCHECK
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Headers
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References
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P00734
(THRB_HUMAN) -
Prothrombin from Homo sapiens
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Seq:
Struc:
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622 a.a.
29 a.a.
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Enzyme class:
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Chains L, H:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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J Biol Chem
266:20085-20093
(1991)
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PubMed id:
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Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors.
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D.W.Banner,
P.Hadváry.
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ABSTRACT
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The mode of binding of four active-site directed inhibitors to human thrombin
has been determined by x-ray crystallographic analysis. The inhibitors studied
are benzamidine, PPACK, NAPAP, and MD-805, of which the last three are compounds
evolved specifically to inhibit thrombin. Crystal structures were determined in
the presence of both the inhibitor and the undecapeptide [des-amino
Asp55]hirudin(55-65) which binds distant from the active site. Despite having
significantly different chemical structures, NAPAP and MD-805 bind to thrombin
in a very similar "inhibitor binding mode" which is not that expected by direct
analogy with the binding of substrate. Both inhibitors bind to thrombin in a
similar way as to trypsin, but thrombin has an extra loop, the "Tyr-Pro-Pro-Trp
loop," not present in trypsin, which gives further binding interactions and is
seen to move somewhat to accommodate binding of the different inhibitors. The
fact that NAPAP and MD-805 require different stereochemistry for potent
inhibition is demonstrated, and its structural basis clarified. The wealth of
data on analogs and variants of these lead compounds is shown to be compatible
with this inhibitor binding mode.
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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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and
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(2006).
Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors.
|
| |
Org Biomol Chem,
4,
2364-2375.
|
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|
PDB codes:
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E.Schweizer,
A.Hoffmann-Röder,
K.Schärer,
J.A.Olsen,
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A fluorine scan at the catalytic center of thrombin: C--F, C--OH, and C--OMe bioisosterism and fluorine effects on pKa and log D values.
|
| |
ChemMedChem,
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611-621.
|
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|
|
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|
|
C.Salvagnini,
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(2005).
Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials.
|
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Org Biomol Chem,
3,
4209-4220.
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PDB code:
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E.Toyota,
H.Sekizaki,
Y.U.Takahashi,
K.Itoh,
and
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Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
|
| |
Chem Pharm Bull (Tokyo),
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|
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|
|
|
|
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S.Akhavan,
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A critical role for Gly25 in the B chain of human thrombin.
|
| |
J Thromb Haemost,
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|
|
|
|
|
|
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S.Kadono,
A.Sakamoto,
Y.Kikuchi,
M.Oh-Eda,
N.Yabuta,
T.Koga,
K.Hattori,
T.Shiraishi,
M.Haramura,
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T.Esaki,
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Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4.
|
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
61,
169-173.
|
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PDB code:
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S.Srivastava,
L.N.Goswami,
and
D.K.Dikshit
(2005).
Progress in the design of low molecular weight thrombin inhibitors.
|
| |
Med Res Rev,
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|
|
|
|
|
|
|
W.Bode
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|
| |
J Thromb Haemost,
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|
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|
|
|
|
|
E.S.Henriques,
N.Fonseca,
and
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(2004).
On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors.
|
| |
Protein Sci,
13,
2355-2369.
|
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|
|
|
|
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M.M.Mueller,
S.Sperl,
J.Stürzebecher,
W.Bode,
and
L.Moroder
(2002).
(R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
|
| |
Biol Chem,
383,
1185-1191.
|
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|
PDB codes:
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N.Budin,
N.Majeux,
and
A.Caflisch
(2001).
Fragment-Based flexible ligand docking by evolutionary optimization.
|
| |
Biol Chem,
382,
1365-1372.
|
|
|
|
|
|
|
N.Majeux,
M.Scarsi,
and
A.Caflisch
(2001).
Efficient electrostatic solvation model for protein-fragment docking.
|
| |
Proteins,
42,
256-268.
|
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|
|
|
|
|
A.Mac Sweeney,
G.Birrane,
M.A.Walsh,
T.O'Connell,
J.P.Malthouse,
and
T.M.Higgins
(2000).
Crystal structure of delta-chymotrypsin bound to a peptidyl chloromethyl ketone inhibitor.
|
| |
Acta Crystallogr D Biol Crystallogr,
56,
280-286.
|
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PDB code:
|
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A.von Matt,
C.Ehrhardt,
P.Burkhard,
R.Metternich,
M.Walkinshaw,
and
C.Tapparelli
(2000).
Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode.
|
| |
Bioorg Med Chem,
8,
2291-2303.
|
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|
|
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|
|
N.Y.Chirgadze,
D.J.Sall,
S.L.Briggs,
D.K.Clawson,
M.Zhang,
G.F.Smith,
and
R.W.Schevitz
(2000).
The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors.
|
| |
Protein Sci,
9,
29-36.
|
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PDB codes:
|
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R.Krishnan,
I.Mochalkin,
R.Arni,
and
A.Tulinsky
(2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
|
| |
Acta Crystallogr D Biol Crystallogr,
56,
294-303.
|
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|
PDB codes:
|
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|
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S.K.Swan,
and
M.J.Hursting
(2000).
The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.
|
| |
Pharmacotherapy,
20,
318-329.
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|
|
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J.Stürzebecher,
V.Magdolen,
W.Bode,
and
L.Moroder
(2000).
Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-ray crystal structure of a trypsin/inhibitor complex and modeling studies.
|
| |
Biol Chem,
381,
321-329.
|
|
|
|
|
|
|
S.Sperl,
U.Jacob,
N.Arroyo de Prada,
J.Stürzebecher,
O.G.Wilhelm,
W.Bode,
V.Magdolen,
R.Huber,
and
L.Moroder
(2000).
(4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase.
|
| |
Proc Natl Acad Sci U S A,
97,
5113-5118.
|
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|
PDB code:
|
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A.Lombardi,
G.De Simone,
S.Galdiero,
N.Staiano,
F.Nastri,
and
V.Pavone
(1999).
From natural to synthetic multisite thrombin inhibitors.
|
| |
Biopolymers,
51,
19-39.
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|
|
|
|
|
A.Scozzafava,
F.Briganti,
and
C.T.Supuran
(1999).
Protease inhibitors - Part 3. Synthesis of non-basic thrombin inhibitors incorporating pyridinium-sulfanilylguanidine moieties at the P1 site.
|
| |
Eur J Med Chem,
34,
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|
|
|
|
|
|
|
H.Jhoti,
A.Cleasby,
S.Reid,
P.J.Thomas,
M.Weir,
and
A.Wonacott
(1999).
Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.
|
| |
Biochemistry,
38,
7969-7977.
|
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|
PDB codes:
|
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|
|
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M.Scarsi,
N.Majeux,
and
A.Caflisch
(1999).
Hydrophobicity at the surface of proteins.
|
| |
Proteins,
37,
565-575.
|
|
|
|
|
|
|
N.Majeux,
M.Scarsi,
J.Apostolakis,
C.Ehrhardt,
and
A.Caflisch
(1999).
Exhaustive docking of molecular fragments with electrostatic solvation.
|
| |
Proteins,
37,
88.
|
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|
|
|
|
|
P.E.Sanderson
(1999).
Small, noncovalent serine protease inhibitors.
|
| |
Med Res Rev,
19,
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W.Jeske,
J.M.Walenga,
B.E.Lewis,
and
J.Fareed
(1999).
Pharmacology of argatroban.
|
| |
Expert Opin Investig Drugs,
8,
625-654.
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|
|
Y.Zhou,
and
M.E.Johnson
(1999).
Comparative molecular modeling analysis of-5-amidinoindole and benzamidine binding to thrombin and trypsin: specific H-bond formation contributes to high 5-amidinoindole potency and selectivity for thrombin and factor Xa.
|
| |
J Mol Recognit,
12,
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|
B.A.Katz,
B.Liu,
M.Barnes,
and
E.B.Springman
(1998).
Crystal structure of recombinant human tissue kallikrein at 2.0 A resolution.
|
| |
Protein Sci,
7,
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E.Skordalakes,
S.Elgendy,
C.A.Goodwin,
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J.M.Freyssinet,
G.Dodson,
and
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(1998).
Bifunctional peptide boronate inhibitors of thrombin: crystallographic analysis of inhibition enhanced by linkage to an exosite 1 binding peptide.
|
| |
Biochemistry,
37,
14420-14427.
|
|
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PDB codes:
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G.De Simone,
A.Lombardi,
S.Galdiero,
F.Nastri,
R.Della Morte,
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M.Bolognesi,
and
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(1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
|
| |
Protein Sci,
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PDB code:
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H.Kubinyi
(1998).
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|
| |
Pharm Unserer Zeit,
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H.Kawamoto,
T.Honma,
T.Iwama,
and
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(1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
|
| |
Proc Natl Acad Sci U S A,
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PDB codes:
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S.Tada,
and
J.J.Blow
(1998).
The replication licensing system.
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| |
Biol Chem,
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|
| |
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| |
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(1996).
Active-site-directed 3D database searching: pharmacophore extraction and validation of hits.
|
| |
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J.Anagli,
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|
| |
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J.Féthière,
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|
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|
| |
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|
|
|
PDB codes:
|
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|
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|
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|
J.M.McDonnell,
A.J.Beavil,
G.A.Mackay,
B.A.Jameson,
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and
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|
| |
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|
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|
P.D.Grootenhuis,
and
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(1996).
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|
| |
J Comput Aided Mol Des,
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|
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|
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T.Poll,
R.Rudolph,
and
W.von der Saal
(1996).
Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: implications for drug design.
|
| |
Structure,
4,
1353-1362.
|
|
|
PDB codes:
|
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|
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|
R.Krishnan,
A.Tulinsky,
G.P.Vlasuk,
D.Pearson,
P.Vallar,
P.Bergum,
T.K.Brunck,
and
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(1996).
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.
|
| |
Protein Sci,
5,
422-433.
|
|
|
PDB code:
|
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|
B.E.Maryanoff,
H.C.Zhang,
M.N.Greco,
K.A.Glover,
J.A.Kauffman,
and
P.Andrade-Gordon
(1995).
Cyclotheonamide derivatives: synthesis and thrombin inhibition. Exploration of specific structure-function issues.
|
| |
Bioorg Med Chem,
3,
1025-1038.
|
|
|
|
|
|
|
D.R.St Laurent,
N.Balasubramanian,
W.T.Han,
A.Trehan,
M.E.Federici,
N.A.Meanwell,
J.J.Wright,
and
S.M.Seiler
(1995).
Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres.
|
| |
Bioorg Med Chem,
3,
1145-1156.
|
|
|
|
|
|
|
W.F.Lau,
L.Tabernero,
J.S.Sack,
and
E.J.Iwanowicz
(1995).
Molecular modeling studies of novel retro-binding tripeptide active-site inhibitors of thrombin.
|
| |
Bioorg Med Chem,
3,
1039-1048.
|
|
|
|
|
|
|
W.T.Han,
A.K.Trehan,
J.J.Wright,
M.E.Federici,
S.M.Seiler,
and
N.A.Meanwell
(1995).
Azetidin-2-one derivatives as inhibitors of thrombin.
|
| |
Bioorg Med Chem,
3,
1123-1143.
|
|
|
|
|
|
|
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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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 |
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