5B25

Crystal structure of human PDE1B with inhibitor 3

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases

Li, P., Zheng, H., Zhao, J., Zhang, L., Yao, W., Zhu, H., Beard, J.D., Ida, K., Lane, W., Snell, G., Sogabe, S., Heyser, C.J., Snyder, G.L., Hendrick, J.P., Vanover, K.E., Davis, R.E., Wennogle, L.P.

(2016) J Med Chem 59: 1149-1164

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01751
  • Primary Citation of Related Structures:  
    5B25

  • PubMed Abstract: 

    A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

    • Organizational Affiliation: 

    Intra-Cellular Therapies, Inc. , 430 East 29th Street, Suite 900, New York, New York 10016, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
A, B, C, D
338Homo sapiensMutation(s): 0 
Gene Names: PDE1B, PDE1B1, PDES1B
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for Q01064 (Homo sapiens)
Explore Q01064 
Go to UniProtKB:  Q01064
PHAROS:  Q01064
GTEx:  ENSG00000123360 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ01064
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4QJ
Query on 4QJ
Download Ideal Coordinates CCD File 
DA [auth D],
G [auth A],
N [auth B],
V [auth C]		(11R,15S)-4-{[4-(6-fluoropyridin-2-yl)phenyl]methyl}-8-methyl-5-(phenylamino)-1,3,4,8,10-pentaazatetracyclo[7.6.0.02,6.011,15]pentadeca-2,5,9-trien-7-one
C29 H26 F N7 O
BBIPVJCGIASXJB-PKTZIBPZSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
EA [auth D]
FA [auth D]
GA [auth D]
H [auth A]
I [auth A]
EA [auth D],
FA [auth D],
GA [auth D],
H [auth A],
I [auth A],
O [auth B],
P [auth B],
W [auth C],
X [auth C],
Y [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
AA [auth C]
HA [auth D]
J [auth A]
K [auth A]
Q [auth B]
AA [auth C],
HA [auth D],
J [auth A],
K [auth A],
Q [auth B],
R [auth B],
S [auth B],
Z [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
BA [auth D],
E [auth A],
L [auth B],
T [auth C]		ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG
Download Ideal Coordinates CCD File 
CA [auth D],
F [auth A],
M [auth B],
U [auth C]		MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4QJ Binding MOAD:  5B25 Ki: 0.06 (nM) from 1 assay(s)
BindingDB:  5B25 IC50: 0.06 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.875α = 90
b = 102.875β = 90
c = 294.848γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-02-03
    Type: Initial release
  • Version 1.1: 2016-02-24
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description