3WS9

Crystal structure of PDE10A in complex with a benzimdazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.346 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.229 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

Chino, A.Masuda, N.Amano, Y.Honbou, K.Mihara, T.Yamazaki, M.Tomishima, M.

(2014) Bioorg Med Chem 22: 3515-3526

  • DOI: https://doi.org/10.1016/j.bmc.2014.04.023
  • Primary Citation of Related Structures:  
    3WS8, 3WS9

  • PubMed Abstract: 

    In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.


  • Organizational Affiliation

    Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayaka.chino@astellas.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
A, B
345Homo sapiensMutation(s): 0 
Gene Names: PDE10A
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y233 (Homo sapiens)
Explore Q9Y233 
Go to UniProtKB:  Q9Y233
PHAROS:  Q9Y233
GTEx:  ENSG00000112541 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y233
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.346 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.229 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.421α = 90
b = 81.542β = 90
c = 161.255γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
AMoREphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-04
    Type: Initial release
  • Version 1.1: 2022-08-24
    Changes: Database references, Derived calculations