4MK7

Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with inhibitor 2 (3-(3-tert-butyl-4-methoxyphenyl)pyridin-2(1H)-one)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B.

Schoenfeld, R.C.Bourdet, D.L.Brameld, K.A.Chin, E.de Vicente, J.Fung, A.Harris, S.F.Lee, E.K.Le Pogam, S.Leveque, V.Li, J.Lui, A.S.Najera, I.Rajyaguru, S.Sangi, M.Steiner, S.Talamas, F.X.Taygerly, J.P.Zhao, J.

(2013) J Med Chem 56: 8163-8182

  • DOI: https://doi.org/10.1021/jm401266k
  • Primary Citation of Related Structures:  
    4MK7, 4MK8, 4MK9, 4MKA, 4MKB

  • PubMed Abstract: 

    Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.


  • Organizational Affiliation

    Pharma Research & Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE
A, B
570Hepatitis C virus (isolate BK)Mutation(s): 0 
Gene Names: NS5B
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.223 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.897α = 90
b = 112.418β = 90
c = 125.926γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-09
    Type: Initial release
  • Version 1.1: 2014-01-15
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations