6N4E

hPGDS complexed with a quinoline-3-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

Deaton, D.N.Do, Y.Holt, J.Jeune, M.R.Kramer, H.F.Larkin, A.L.Orband-Miller, L.A.Peckham, G.E.Poole, C.Price, D.J.Schaller, L.T.Shen, Y.Shewchuk, L.M.Stewart, E.L.Stuart, J.D.Thomson, S.A.Ward, P.Wilson, J.W.Xu, T.Guss, J.H.Musetti, C.Rendina, A.R.Affleck, K.Anders, D.Hancock, A.P.Hobbs, H.Hodgson, S.T.Hutchinson, J.Leveridge, M.V.Nicholls, H.Smith, I.E.D.Somers, D.O.Sneddon, H.F.Uddin, S.Cleasby, A.Mortenson, P.N.Richardson, C.Saxty, G.

(2019) Bioorg Med Chem 27: 1456-1478

  • DOI: https://doi.org/10.1016/j.bmc.2019.02.017
  • Primary Citation of Related Structures:  
    6N4E, 6N69

  • PubMed Abstract: 

    With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC 50  = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC 50  = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC 50  = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD 2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.


  • Organizational Affiliation

    GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. Electronic address: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hematopoietic prostaglandin D synthase200Homo sapiensMutation(s): 0 
Gene Names: HPGDSGSTSPGDSPTGDS2
EC: 5.3.99.2 (PDB Primary Data), 2.5.1.18 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for O60760 (Homo sapiens)
Explore O60760 
Go to UniProtKB:  O60760
PHAROS:  O60760
GTEx:  ENSG00000163106 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60760
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KCD (Subject of Investigation/LOI)
Query on KCD

Download Ideal Coordinates CCD File 
C [auth A]7-(difluoromethoxy)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]quinoline-3-carboxamide
C20 H24 F2 N2 O3
YRWMWDLEUYLURJ-SHTZXODSSA-N
GSH
Query on GSH

Download Ideal Coordinates CCD File 
B [auth A]GLUTATHIONE
C10 H17 N3 O6 S
RWSXRVCMGQZWBV-WDSKDSINSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KCD BindingDB:  6N4E Kd: 0.5 (nM) from 1 assay(s)
IC50: 9.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.599α = 90
b = 72.76β = 90
c = 93.985γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
REFMACrefinement
PDB_EXTRACTdata extraction
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-27
    Type: Initial release
  • Version 1.1: 2019-04-10
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references