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PDBsum entry 1kts
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Hydrolase/hydrolase inhibitor PDB id
1kts

 

 

 

 

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Contents
Protein chains
27 a.a. *
252 a.a. *
Ligands
ASP-PHE-GLU-GLU-
ILE-PRO-GLU-GLU-
TYS-LEU
C24
Waters ×135
* Residue conservation analysis
PDB id:
1kts
Name: Hydrolase/hydrolase inhibitor
Title: Thrombin inhibitor complex
Structure: Thrombin. Chain: a. Fragment: light chain. Synonym: coagulation factor ii, alpha thrombin. Thrombin. Chain: b. Fragment: heavy chain. Synonym: coagulation factor ii, alpha thrombin. Hirudin iib.
Source: Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421
Biol. unit: Trimer (from PQS)
Resolution:
2.40Å     R-factor:   0.211     R-free:   0.309
Authors: H.Nar
Key ref: N.H.Hauel et al. (2002). Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem, 45, 1757-1766. PubMed id: 11960487 DOI: 10.1021/jm0109513
Date:
17-Jan-02     Release date:   06-Feb-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
27 a.a.
Protein chain
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
252 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
DOI no: 10.1021/jm0109513 J Med Chem 45:1757-1766 (2002)
PubMed id: 11960487  
 
 
Structure-based design of novel potent nonpeptide thrombin inhibitors.
N.H.Hauel, H.Nar, H.Priepke, U.Ries, J.M.Stassen, W.Wienen.
 
  ABSTRACT  
 
The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21374633 H.G.Wallnoefer, K.R.Liedl, and T.Fox (2011).
A challenging system: Free energy prediction for factor Xa.
  J Comput Chem, 32, 1743-1752.  
21254865 M.A.Giorgi, H.Cohen Arazi, C.D.Gonzalez, and G.Di Girolamo (2011).
Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban.
  Expert Opin Pharmacother, 12, 567-577.  
20148287 O.Nicolotti, I.Giangreco, T.F.Miscioscia, M.Convertino, F.Leonetti, L.Pisani, and A.Carotti (2010).
Screening of benzamidine-based thrombin inhibitors via a linear interaction energy in continuum electrostatics model.
  J Comput Aided Mol Des, 24, 117-129.  
18956996 B.E.Baetz, and S.A.Spinler (2008).
Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.
  Pharmacotherapy, 28, 1354-1373.  
18591978 B.I.Eriksson, H.Smith, U.Yasothan, and P.Kirkpatrick (2008).
Dabigatran etexilate.
  Nat Rev Drug Discov, 7, 557-558.  
18778188 H.Nishio, M.Ieko, and T.Nakabayashi (2008).
New therapeutic option for thromboembolism--dabigatran etexilate.
  Expert Opin Pharmacother, 9, 2509-2517.  
18594479 M.Hammwöhner, and A.Goette (2008).
Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation.
  J Cardiovasc Pharmacol, 52, 18-27.  
  19337550 M.R.Lassen, and V.Laux (2008).
Emergence of new oral antithrombotics: a critical appraisal of their clinical potential.
  Vasc Health Risk Manag, 4, 1373-1386.  
17909797 S.Ugurel, D.Schrama, G.Keller, D.Schadendorf, E.B.Bröcker, R.Houben, M.Zapatka, W.Fink, H.L.Kaufman, and J.C.Becker (2008).
Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy.
  Cancer Immunol Immunother, 57, 685-691.  
17541992 A.Stürzebecher, D.Dönnecke, A.Schweinitz, O.Schuster, P.Steinmetzer, U.Stürzebecher, J.Kotthaus, B.Clement, J.Stürzebecher, and T.Steinmetzer (2007).
Highly potent and selective substrate analogue factor xa inhibitors containing d-homophenylalanine analogues as p3 residue: part 2.
  ChemMedChem, 2, 1043-1053.  
17869635 B.I.Eriksson, O.E.Dahl, N.Rosencher, A.A.Kurth, C.N.van Dijk, S.P.Frostick, M.H.Prins, R.Hettiarachchi, S.Hantel, J.Schnee, and H.R.Büller (2007).
Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
  Lancet, 370, 949-956.  
17764540 B.I.Eriksson, O.E.Dahl, N.Rosencher, A.A.Kurth, C.N.van Dijk, S.P.Frostick, P.Kälebo, A.V.Christiansen, S.Hantel, R.Hettiarachchi, J.Schnee, and H.R.Büller (2007).
Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
  J Thromb Haemost, 5, 2178-2185.  
17685615 C.C.Liu, E.Brustad, W.Liu, and P.G.Schultz (2007).
Crystal structure of a biosynthetic sulfo-hirudin complexed to thrombin.
  J Am Chem Soc, 129, 10648-10649.
PDB code: 2pw8
18019535 D.Blomberg, T.Fex, Y.Xue, K.Brickmann, and J.Kihlberg (2007).
Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
  Org Biomol Chem, 5, 2599-2605.
PDB code: 2pks
17362226 W.Wienen, J.M.Stassen, H.Priepke, U.J.Ries, and N.Hauel (2007).
Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis.
  J Thromb Haemost, 5, 1237-1242.  
16923023 B.E.Maryanoff, D.F.McComsey, M.J.Costanzo, S.C.Yabut, T.Lu, M.R.Player, E.C.Giardino, and B.P.Damiano (2006).
Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa.
  Chem Biol Drug Des, 68, 29-36.  
16906775 B.I.Eriksson, and D.J.Quinlan (2006).
Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.
  Drugs, 66, 1411-1429.  
  16687960 J.I.Weitz (2006).
Changing paradigms in the management of venous thromboembolism.
  Am Heart Hosp J, 4, 135-141.  
15635223 E.Toyota, H.Sekizaki, Y.U.Takahashi, K.Itoh, and K.Tanizawa (2005).
Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
  Chem Pharm Bull (Tokyo), 53, 22-26.  
15253941 P.R.Sinnaeve, and F.J.Van de Werf (2004).
Will oral antithrombin agents replace warfarin?
  Heart, 90, 827-828.  
12720490 J.Ruef, and H.A.Katus (2003).
New antithrombotic drugs on the horizon.
  Expert Opin Investig Drugs, 12, 781-797.  
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.

 

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