4AA5

P38ALPHA MAP KINASE BOUND TO CMPD 33

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history. 


Literature

The Discovery of N-Cyclopropyl-4-Methyl-3-[6--(4-Methylpiperazin-1-Yl-4-Oxoquinazolin-3(4H)-Yl]Benzamide (Azd6703), a Clinical P38Alpha Map Kinase Inhibitor for the Treatment of Inflammatory Diseases

Brown, D.S., Cumming, J.G., Bethel, P., Finlayson, J., Gerhardt, S., Nash, I., Pauptit, R., Pike, K.G., Reid, A., Snelson, W., Swallow, S., Thompson, C.

(2012) Bioorg Med Chem Lett 22: 3879

  • DOI: https://doi.org/10.1016/j.bmcl.2012.04.116
  • Primary Citation of Related Structures:  
    4A9Y, 4AA0, 4AA4, 4AA5, 4AAC

  • PubMed Abstract: 

    A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.

    • Organizational Affiliation: 

    AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MITOGEN-ACTIVATED PROTEIN KINASE 14365Homo sapiensMutation(s): 0 
EC: 2.7.11.24 (PDB Primary Data), 2.7.1.37 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NQB
Query on NQB
Download Ideal Coordinates CCD File 
B [auth A]N-CYCLOPROPYL-4-METHYL-3-[6-(4-METHYLPIPERAZIN-1-YL)-4-OXIDANYLIDENE-QUINAZOLIN-3-YL]BENZAMIDE
C24 H27 N5 O2
ZMAZXHICVRYLQN-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSS
Query on CSS
A
L-PEPTIDE LINKINGC3 H7 N O2 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
NQB BindingDB:  4AA5 IC50: min: 15.85, max: 50 (nM) from 7 assay(s)
PDBBind:  4AA5 IC50: 16 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.48α = 90
b = 74.654β = 90
c = 76.399γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-16
    Type: Initial release
  • Version 1.1: 2012-06-06
    Changes: Other
  • Version 1.2: 2017-06-28
    Changes: Data collection
  • Version 1.3: 2019-01-30
    Changes: Data collection, Experimental preparation
  • Version 1.4: 2019-02-06
    Changes: Data collection, Experimental preparation
  • Version 1.5: 2024-11-13
    Changes: Data collection, Database references, Derived calculations, Other, Structure summary