3W5E

Crystal structure of phosphodiesterase 4B in complex with compound 31e


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors

Goto, T.Shiina, A.Yoshino, T.Mizukami, K.Hirahara, K.Suzuki, O.Sogawa, Y.Takahashi, T.Mikkaichi, T.Nakao, N.Takahashi, M.Hasegawa, M.Sasaki, S.

(2013) Bioorg Med Chem Lett 23: 3325-3328

  • DOI: https://doi.org/10.1016/j.bmcl.2013.03.104
  • Primary Citation of Related Structures:  
    3W5E

  • PubMed Abstract: 

    2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.


  • Organizational Affiliation

    R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Tokyo 140-8710, Japan. goto.taiji.kt@daiichisankyo.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
A, B
377Homo sapiensMutation(s): 0 
Gene Names: DPDE4PDE4B
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for Q07343 (Homo sapiens)
Explore Q07343 
Go to UniProtKB:  Q07343
PHAROS:  Q07343
GTEx:  ENSG00000184588 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07343
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
NVW PDBBind:  3W5E IC50: 11 (nM) from 1 assay(s)
BindingDB:  3W5E IC50: 11 (nM) from 1 assay(s)
Binding MOAD:  3W5E IC50: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.064α = 90
b = 158.19β = 90
c = 58.157γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-29
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Refinement description
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description