4JVQ

Crystal structure of hcv ns5b polymerase in complex with compound 9


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Enantiomeric Atropisomers Inhibit HCV Polymerase and/or HIV Matrix: Characterizing Hindered Bond Rotations and Target Selectivity.

Laplante, S.R.Forgione, P.Boucher, C.Coulombe, R.Gillard, J.Hucke, O.Jakalian, A.Joly, M.A.Kukolj, G.Lemke, C.McCollum, R.Titolo, S.Beaulieu, P.L.Stammers, T.

(2014) J Med Chem 57: 1944-1951

  • DOI: https://doi.org/10.1021/jm401202a
  • Primary Citation of Related Structures:  
    4JMU, 4JVQ

  • PubMed Abstract: 

    An anthranilic acid series of allosteric thumb pocket 2 HCV NS5B polymerase inhibitors exhibited hindered rotation along a covalent bond axis, and the existence of atropisomer chirality was confirmed by NMR, HPLC analysis on chiral supports, and computational studies. A thorough understanding of the concerted rotational properties and the influence exerted by substituents involved in this steric phenomenon was attained through biophysical studies on a series of truncated analogues. The racemization half-life of a compound within this series was determined to be 69 min, which was consistent with a class 2 atropisomer (intermediate conformational exchange). It was further found by X-ray crystallography that one enantiomer of a compound bound to the intended HCV NS5B polymerase target whereas the mirror image atropisomer was able to bind to an unrelated HIV matrix target. Analogues were then identified that selectively inhibited the former. These studies highlight that atropisomer chirality can lead to distinct entities with specific properties, and the phenomenon of atropisomerism in drug discovery should be evaluated and appropriately managed.


  • Organizational Affiliation

    Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval , Quebec H7S 2G5, Canada.


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
1ML
Query on 1ML

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
5-{4-[(4-methoxybenzoyl)amino]phenoxy}-2-{[(trans-4-methylcyclohexyl)carbonyl](propan-2-yl)amino}benzoic acid
C32 H36 N2 O6
QTXXVFNPTKTUBW-AFARHQOCSA-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
1ML Binding MOAD:  4JVQ IC50: 630 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.12α = 90
b = 108.02β = 90
c = 135.42γ = 90
Software Package:
Software NamePurpose
CNXrefinement
XDSdata reduction
XDSdata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-02-05 
  • Deposition Author(s): Coulombe, R.

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-05
    Type: Initial release
  • Version 1.1: 2014-03-26
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description