2WHO

CRYSTAL STRUCTURE OF HEPATITIS C VIRUS NS5B POLYMERASE FROM 1B GENOTYPE IN COMPLEX WITH A NON-NUCLEOSIDE INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors.

Ontoria, J.M.Rydberg, E.H.Di Marco, S.Tomei, L.Attenni, B.Malancona, S.Martin Hernando, J.I.Gennari, N.Koch, U.Narjes, F.Rowley, M.Summa, V.Carroll, S.S.Olsen, D.B.De Francesco, R.Altamura, S.Migliaccio, G.Carfi, A.

(2009) J Med Chem 52: 5217-5227

  • DOI: https://doi.org/10.1021/jm900517t
  • Primary Citation of Related Structures:  
    2WHO

  • PubMed Abstract: 

    The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.


  • Organizational Affiliation

    Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti, S.p.A. (IRBM-MRL Rome), Via Pontina Km 30,600, I-00040 Pomezia, Italy. jesus_ontoria@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE
A, B
536Hepatitis C virus (isolate BK)Mutation(s): 0 
EC: 2.7.7.48
UniProt
Find proteins for P26663 (Hepatitis C virus genotype 1b (isolate BK))
Explore P26663 
Go to UniProtKB:  P26663
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26663
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
VGI BindingDB:  2WHO IC50: min: 20, max: 1000 (nM) from 6 assay(s)
EC50: 7100 (nM) from 1 assay(s)
Binding MOAD:  2WHO IC50: 20 (nM) from 1 assay(s)
PDBBind:  2WHO IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.21α = 90
b = 96.999β = 90
c = 193.762γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-08-11 
  • Deposition Author(s): Di Marco, S.

Revision History  (Full details and data files)

  • Version 1.0: 2009-08-11
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 2.0: 2019-01-23
    Changes: Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description