2FEQ

orally active thrombin inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety

Mack, H.Baucke, D.Hornberger, W.Lange, U.E.W.Seitz, W.Hoeffken, H.W.

(2006) Bioorg Med Chem Lett 16: 2641-2647

  • DOI: https://doi.org/10.1016/j.bmcl.2006.02.040
  • Primary Citation of Related Structures:  
    2FEQ, 2FES

  • PubMed Abstract: 

    The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.


  • Organizational Affiliation

    Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. helmut.mack@abbott.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thrombin light chainA [auth L]36Homo 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
Thrombin heavy chainB [auth H]259Homo 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
Decapeptide Hirudin AnalogueC [auth D]11Hirudo medicinalisMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
34P
Query on 34P

Download Ideal Coordinates CCD File 
D [auth H]N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({4-[(E)-AMINO(IMINO)METHYL]-1,3-THIAZOL-2-YL}METHYL)-L-PROLINAMIDE
C21 H32 N6 O4 S
MIEXIWNUQBMNML-ZBFHGGJFSA-N
Modified Residues  3 Unique
IDChains TypeFormula2D DiagramParent
ALC
Query on ALC
C [auth D]L-PEPTIDE LINKINGC9 H17 N O2ALA
HYP
Query on HYP
C [auth D]L-PEPTIDE LINKINGC5 H9 N O3PRO
SMF
Query on SMF
C [auth D]L-PEPTIDE LINKINGC10 H13 N O5 SPHE
Binding Affinity Annotations 
IDSourceBinding Affinity
34P PDBBind:  2FEQ IC50: 1.39 (nM) from 1 assay(s)
Binding MOAD:  2FEQ IC50: 1.39 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 2 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.44 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.185 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.24α = 90
b = 72.39β = 101.01
c = 73.06γ = 90
Software Package:
Software NamePurpose
SAINTdata scaling
X-GENdata reduction
CNXrefinement
SAINTdata reduction
X-GENdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-08-08
    Type: Initial release
  • Version 1.1: 2008-05-01
    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: 2017-10-18
    Changes: Refinement description
  • Version 1.5: 2018-04-04
    Changes: Data collection