1KTS

Thrombin Inhibitor Complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structure-based design of novel potent nonpeptide thrombin inhibitors.

Hauel, N.H.Nar, H.Priepke, H.Ries, U.Stassen, J.M.Wienen, W.

(2002) J Med Chem 45: 1757-1766

  • DOI: https://doi.org/10.1021/jm0109513
  • Primary Citation of Related Structures:  
    1KTS, 1KTT

  • PubMed 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.


  • Organizational Affiliation

    Boehringer Ingelheim Pharma KG, Research Division, Birkendorfer Strasse 65, D-88397 Biberach/RISS, Germany. norbert.hauel@bc.boehringer-ingelheim.de


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
thrombin36Homo sapiensMutation(s): 0 
EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
thrombin259Homo sapiensMutation(s): 0 
EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
hirudin IIB11Hirudo medicinalisMutation(s): 0 
UniProt
Find proteins for P28504 (Hirudo medicinalis)
Explore P28504 
Go to UniProtKB:  P28504
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28504
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C24
Query on C24

Download Ideal Coordinates CCD File 
D [auth B]3-({2-[(4-CARBAMIMIDOYL-PHENYLAMINO)-METHYL]-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBONYL}-PYRIDIN-2-YL-AMINO)-PROPIONIC ACID ETHYL ESTER
C27 H29 N7 O3
BGLLICFSSKPUMR-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TYS
Query on TYS
C
L-PEPTIDE LINKINGC9 H11 N O6 STYR
Binding Affinity Annotations 
IDSourceBinding Affinity
C24 Binding MOAD:  1KTS Ki: 4.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.9α = 90
b = 71β = 99.8
c = 72.2γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2002-02-06 
  • Deposition Author(s): Nar, H.

Revision History  (Full details and data files)

  • Version 1.0: 2002-02-06
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2013-03-13
    Changes: Other