3H5S

Hepatitis C virus polymerase NS5B with saccharin inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 

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 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides

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.Adjabeng, G.Elworthy, T.R.Li, J.Wang, B.Bamberg, J.T.Harris, S.F.Wong, A.Leveque, V.J.Najera, I.Le Pogam, S.Rajyaguru, S.Ao-Ieong, G.Alexandrova, L.Larrabee, S.Brandl, M.Briggs, A.Sukhtankar, S.Farrell, R.

(2009) Bioorg Med Chem Lett 19: 5652-5656

  • DOI: https://doi.org/10.1016/j.bmcl.2009.08.022
  • Primary Citation of Related Structures:  
    3H5S, 3H5U

  • PubMed Abstract: 

    A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.


  • 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
H5S
Query on H5S

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(5S)-5-tert-butyl-1-(4-fluoro-3-methylbenzyl)-4-hydroxy-3-[8-(methylsulfonyl)-1,1-dioxido-6,7,8,9-tetrahydroisothiazolo[4,5-h]isoquinolin-3-yl]-1,5-dihydro-2H-pyrrol-2-one
C27 H30 F N3 O6 S2
YRWZNTIWOPXYQZ-RUZDIDTESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
H5S PDBBind:  3H5S IC50: 5 (nM) from 1 assay(s)
Binding MOAD:  3H5S IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.631α = 90
b = 105.803β = 90
c = 125.632γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

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