4X2K

Selection of fragments for kinase inhibitor design: decoration is key


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.167 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selection of fragments for kinase inhibitor design: decoration is key.

Czodrowski, P.Holzemann, G.Barnickel, G.Greiner, H.Musil, D.

(2015) J Med Chem 58: 457-465

  • DOI: https://doi.org/10.1021/jm501597j
  • Primary Citation of Related Structures:  
    4X0M, 4X2F, 4X2G, 4X2J, 4X2K, 4X2N, 4X3J

  • PubMed Abstract: 

    In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor β receptor type 1 kinase domain were determined by X-ray crystallography. Three different binding modes of the fragments are observed that depend on the position and the type of the substitution at the core fragment. The influence of different substituents on the preferred fragment pose was analyzed by various computational approaches. We postulate that the replacement of water molecules leads to the different binding modes.


  • Organizational Affiliation

    Discovery Technologies, Merck Serono Research, Merck Serono R&D, Merck KGaA , Frankfurter Strasse 250, 64293 Darmstadt, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TGF-beta receptor type-1305Homo sapiensMutation(s): 0 
Gene Names: TGFBR1ALK5SKR4
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for P36897 (Homo sapiens)
Explore P36897 
Go to UniProtKB:  P36897
PHAROS:  P36897
GTEx:  ENSG00000106799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP36897
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3WO
Query on 3WO

Download Ideal Coordinates CCD File 
B [auth A]4-[(3-aminophenyl)amino]pyrido[2,3-d]pyrimidin-5(6H)-one
C13 H11 N5 O
PWIXWXGXVKPITN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.167 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.31α = 90
b = 77.51β = 90
c = 90.2γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata 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: 2014-12-24
    Type: Initial release
  • Version 1.1: 2015-01-21
    Changes: Database references
  • Version 1.2: 2024-05-08
    Changes: Data collection, Database references