2O8H

Crystal structure of the catalytic domain of rat phosphodiesterase 10A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.227 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors

Chappie, T.A.Humphrey, J.M.Allen, M.P.Estep, K.G.Fox, C.B.Lebel, L.A.Liras, S.Marr, E.S.Menniti, F.S.Pandit, J.Schmidt, C.J.Tu, M.Williams, R.D.Yang, F.V.

(2007) J Med Chem 50: 182-185

  • DOI: https://doi.org/10.1021/jm060653b
  • Primary Citation of Related Structures:  
    2O8H, 2OVV, 2OVY

  • PubMed Abstract: 

    A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.


  • Organizational Affiliation

    CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. thomas.a.chappie@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphodiesterase-10A362Rattus norvegicusMutation(s): 0 
Gene Names: Pde10aPDE10A
EC: 3.1.4.17
UniProt
Find proteins for Q9QYJ6 (Rattus norvegicus)
Explore Q9QYJ6 
Go to UniProtKB:  Q9QYJ6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9QYJ6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
227
Query on 227

Download Ideal Coordinates CCD File 
D [auth A]6,7-DIMETHOXY-4-{8-[(4-METHYLPIPERAZIN-1-YL)SULFONYL]-3,4-DIHYDROISOQUINOLIN-2(1H)-YL}QUINAZOLINE
C24 H29 N5 O4 S
XOFGGFSZAJCEEW-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
227 BindingDB:  2O8H Ki: 25 (nM) from 1 assay(s)
Binding MOAD:  2O8H Ki: 25 (nM) from 1 assay(s)
PDBBind:  2O8H Ki: 25 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.227 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.622α = 90
b = 120.622β = 90
c = 82.143γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-01-09
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2023-12-27
    Changes: Data collection, Database references, Derived calculations