6B96

Crystal Structure of PDE2 in complex with compound 16


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design.

Forster, A.B.Abeywickrema, P.Bunda, J.Cox, C.D.Cabalu, T.D.Egbertson, M.Fay, J.Getty, K.Hall, D.Kornienko, M.Lu, J.Parthasarathy, G.Reid, J.Sharma, S.Shipe, W.D.Smith, S.M.Soisson, S.Stachel, S.J.Su, H.P.Wang, D.Berger, R.

(2017) Bioorg Med Chem Lett 27: 5167-5171

  • DOI: https://doi.org/10.1016/j.bmcl.2017.10.054
  • Primary Citation of Related Structures:  
    6B96, 6B97, 6B98

  • PubMed Abstract: 

    We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (K i  = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.


  • Organizational Affiliation

    Discovery Chemistry, MRL, 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: Ashley_nomland@merck.com.


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
CZV
Query on CZV

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
6-chloro-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine
C15 H11 Cl F3 N5
NFRLPPZMBPDGMI-UHFFFAOYSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CZV Binding MOAD:  6B96 Ki: 14.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.33α = 90
b = 96.71β = 90
c = 102.35γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
autoPROCdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-11-22 
  • Deposition Author(s): Lu, J.

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-22
    Type: Initial release
  • Version 1.1: 2017-11-29
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description