5K32

PDE4D crystal structure in complex with small molecule inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships.

Roberts, R.S.Sevilla, S.Ferrer, M.Taltavull, J.Hernandez, B.Segarra, V.Gracia, J.Lehner, M.D.Gavalda, A.Andres, M.Cabedo, J.Vilella, D.Eichhorn, P.Calama, E.Carcasona, C.Miralpeix, M.

(2018) J Med Chem 61: 2472-2489

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01751
  • Primary Citation of Related Structures:  
    5K32

  • PubMed Abstract: 

    Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.


  • Organizational Affiliation

    Medicinal Chemistry & Screening , ‡Pharmacokinetics & Metabolism , and §Experimental Dermatology , Almirall S.A., Centro de Investigación y Desarrollo , Crta. Laureà Miró 408-410 , Sant Feliu de Llobregat, 08980 Barcelona , Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
A, B
325Homo sapiensMutation(s): 0 
Gene Names: PDE4DDPDE3
EC: 3.1.4.53
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens)
Explore Q08499 
Go to UniProtKB:  Q08499
PHAROS:  Q08499
GTEx:  ENSG00000113448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08499
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6Q2
Query on 6Q2

Download Ideal Coordinates CCD File 
E [auth A],
X [auth B]
4-[(3-methoxyphenyl)amino]-2-phenyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one
C21 H19 N3 O2
PBJZBHKLXZKPND-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
V [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
CA [auth B]
DA [auth B]
EA [auth B]
AA [auth B],
BA [auth B],
CA [auth B],
DA [auth B],
EA [auth B],
F [auth A],
FA [auth B],
G [auth A],
GA [auth B],
H [auth A],
HA [auth B],
I [auth A],
IA [auth B],
J [auth A],
JA [auth B],
K [auth A],
KA [auth B],
L [auth A],
LA [auth B],
M [auth A],
MA [auth B],
N [auth A],
NA [auth B],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
W [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.967α = 90
b = 79.739β = 90
c = 163.845γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
SCALAdata 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: 2017-03-29
    Type: Initial release
  • Version 1.1: 2018-03-21
    Changes: Advisory, Database references
  • Version 1.2: 2018-04-04
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-10
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description