3H59

Hepatitis C virus polymerase NS5B with thiazine inhibitor 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids

de Vicente, J.Hendricks, R.T.Smith, D.B.Fell, J.B.Fischer, J.Spencer, S.R.Stengel, P.J.Mohr, P.Robinson, J.E.Blake, J.F.Hilgenkamp, R.K.Yee, C.Zhao, J.Elworthy, T.R.Tracy, J.Chin, E.Li, J.Lui, A.Wang, B.Oshiro, C.Harris, S.F.Ghate, M.Leveque, V.J.Najera, I.Le Pogam, S.Rajyaguru, S.Ao-Ieong, G.Alexandrova, L.Fitch, B.Brandl, M.Masjedizadeh, M.Wu, S.Y.de Keczer, S.Voronin, T.

(2009) Bioorg Med Chem Lett 19: 5648-5651

  • DOI: https://doi.org/10.1016/j.bmcl.2009.08.023
  • Primary Citation of Related Structures:  
    3H59

  • PubMed Abstract: 

    Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.


  • Organizational Affiliation

    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. javier.devicente@roche.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
576Hepatitis 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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
H59
Query on H59

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{3-[(5S)-5-(1,1-dimethylpropyl)-1-(4-fluoro-3-methylbenzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxido-4H-1,4-benzothiazin-7-yl}methanesulfonamide
C26 H30 F N3 O6 S2
FIWSMJXHIVIUAK-XMMPIXPASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
H59 PDBBind:  3H59 IC50: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.855α = 90
b = 106.417β = 90
c = 127.195γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-09-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance