5LP1

CRYSTAL STRUCTURE OF HUMAN LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 IN COMPLEX WITH A [1.1.1]BICYCLOPENTANE-CONTAINING INHIBITOR AT 1.91A RESOLUTION.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor.

Measom, N.D.Down, K.D.Hirst, D.J.Jamieson, C.Manas, E.S.Patel, V.K.Somers, D.O.

(2017) ACS Med Chem Lett 8: 43-48

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00281
  • Primary Citation of Related Structures:  
    5LP1

  • PubMed Abstract: 

    We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA 2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.


  • Organizational Affiliation

    GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Platelet-activating factor acetylhydrolase388Homo sapiensMutation(s): 0 
Gene Names: PLA2G7PAFAH
EC: 3.1.1.47
UniProt & NIH Common Fund Data Resources
Find proteins for Q13093 (Homo sapiens)
Explore Q13093 
Go to UniProtKB:  Q13093
PHAROS:  Q13093
GTEx:  ENSG00000146070 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13093
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
71H
Query on 71H

Download Ideal Coordinates CCD File 
D [auth A]~{N}-[2-(diethylamino)ethyl]-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxidanylidene-5~{H}-cyclopenta[d]pyrimidin-1-yl]-~{N}-[[3-[4-(trifluoromethyl)phenyl]-1-bicyclo[1.1.1]pentanyl]methyl]ethanamide
C35 H38 F4 N4 O2 S
SHVFOCPBEIJQSO-AQOUDTPCSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
71H Binding MOAD:  5LP1 IC50: 0.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 100.28α = 90
b = 91.56β = 111.88
c = 51.65γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
REFMACphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-02-01 
  • Deposition Author(s): Somers, D.

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-01
    Type: Initial release
  • Version 1.1: 2019-06-12
    Changes: Data collection, Structure summary