4JJU

Crystal structure of HCV NS5B polymerase in complex with COMPOUND 29


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype.

Beaulieu, P.L.Coulombe, R.Duan, J.Fazal, G.Godbout, C.Hucke, O.Jakalian, A.Joly, M.A.Lepage, O.Llinas-Brunet, M.Naud, J.Poirier, M.Rioux, N.Thavonekham, B.Kukolj, G.Stammers, T.A.

(2013) Bioorg Med Chem Lett 23: 4132-4140

  • DOI: https://doi.org/10.1016/j.bmcl.2013.05.037
  • Primary Citation of Related Structures:  
    4JJS, 4JJU

  • PubMed Abstract: 

    We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.


  • Organizational Affiliation

    Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. resgeneral.lav@boehringer-ingelheim.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Genome polyprotein
A, B
576Hepatitis C virus isolate HC-J4Mutation(s): 0 
Gene Names: NS5B
EC: 3.4.22 (PDB Primary Data), 3.4.21.98 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.6.4.13 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for O92972 (Hepatitis C virus genotype 1b (strain HC-J4))
Explore O92972 
Go to UniProtKB:  O92972
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO92972
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1MB
Query on 1MB

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
1-(2,4-difluorobenzyl)-6-{[3-(trifluoromethyl)pyridin-2-yl]oxy}quinazolin-4(1H)-one
C21 H12 F5 N3 O2
SWXDHFLZCMRYEP-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
I [auth B],
J [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1MB PDBBind:  4JJU IC50: 510 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 107.07α = 90
b = 108.39β = 90
c = 134.88γ = 90
Software Package:
Software NamePurpose
CNXrefinement
XDSdata reduction
XDSdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-06-12 
  • Deposition Author(s): Coulombe, R.

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-12
    Type: Initial release
  • Version 1.1: 2013-07-10
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations