2VIQ

Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator.

Frederickson, M.Callaghan, O.Chessari, G.Congreve, M.Cowan, S.R.Matthews, J.E.Mcmenamin, R.Smith, D.Vinkovic, M.Wallis, N.G.

(2008) J Med Chem 51: 183

  • DOI: https://doi.org/10.1021/jm701359z
  • Primary Citation of Related Structures:  
    2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, 2VIW

  • PubMed Abstract: 

    Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.


  • Organizational Affiliation

    Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
UROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B253Homo sapiensMutation(s): 2 
EC: 3.4.21.73
UniProt & NIH Common Fund Data Resources
Find proteins for P00749 (Homo sapiens)
Explore P00749 
Go to UniProtKB:  P00749
PHAROS:  P00749
GTEx:  ENSG00000122861 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00749
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D55
Query on D55

Download Ideal Coordinates CCD File 
C [auth A]4-(2-aminoethoxy)-N-(2,5-diethoxyphenyl)-3,5-dimethylbenzamide
C21 H28 N2 O4
PHTPPZCTHZHCQD-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
B [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
D55 BindingDB:  2VIQ IC50: 1300 (nM) from 1 assay(s)
PDBBind:  2VIQ IC50: 1300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.176α = 90
b = 53.949β = 90
c = 81.756γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
d*TREKdata reduction
d*TREKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-01-22
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-07-05
    Changes: Data collection