6CYD

PDE2 in complex with compound 7

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history. 


Literature

Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.

Stachel, S.J., Berger, R., Nomland, A.B., Ginnetti, A.T., Paone, D.V., Wang, D., Puri, V., Lange, H., Drott, J., Lu, J., Marcus, J., Dwyer, M.P., Suon, S., Uslaner, J.M., Smith, S.M.

(2018) ACS Med Chem Lett 9: 815-820

  • DOI: https://doi.org/10.1021/acsmedchemlett.8b00214
  • Primary Citation of Related Structures:  
    6CYB, 6CYC, 6CYD

  • PubMed Abstract: 

    Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3 , while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4 , demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

    • Organizational Affiliation: 

    Merck & Co. Inc., P.O. Box 4, West Point, Pennsylvania 19486, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cGMP-dependent 3',5'-cyclic phosphodiesterase
A, B
373Homo sapiensMutation(s): 0 
Gene Names: PDE2A
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for O00408 (Homo sapiens)
Explore O00408 
Go to UniProtKB:  O00408
PHAROS:  O00408
GTEx:  ENSG00000186642 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00408
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FKG (Subject of Investigation/LOI)
Query on FKG
Download Ideal Coordinates CCD File 
E [auth A],
J [auth B]		3-(hydroxymethyl)-6-methyl-1-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
C16 H15 F3 N4 O2
WOPONWMJGIDXSF-QMMMGPOBSA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]		ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
K [auth B]		1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG
Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]		MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FKG Binding MOAD:  6CYD IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.94α = 90
b = 91.82β = 90
c = 102.83γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
autoPROCdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2018-09-19 
    • Deposition Author(s): Lu, J.

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-19
    Type: Initial release
  • Version 1.1: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description