3HHK

HCV NS5b polymerase complex with a substituted benzothiadizine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase.

Shaw, A.N.Tedesco, R.Bambal, R.Chai, D.Concha, N.O.Darcy, M.G.Dhanak, D.Duffy, K.J.Fitch, D.M.Gates, A.Johnston, V.K.Keenan, R.M.Lin-Goerke, J.Liu, N.Sarisky, R.T.Wiggall, K.J.Zimmerman, M.N.

(2009) Bioorg Med Chem Lett 19: 4350-4353

  • DOI: https://doi.org/10.1016/j.bmcl.2009.05.091
  • Primary Citation of Related Structures:  
    3HHK

  • PubMed Abstract: 

    The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.


  • Organizational Affiliation

    Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HCV NS5 polymerase
A, B
563Hepatitis C virus subtype 1bMutation(s): 0 
UniProt
Find proteins for Q99AU2 (Hepatitis C virus subtype 1b)
Explore Q99AU2 
Go to UniProtKB:  Q99AU2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99AU2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
77Z
Query on 77Z

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
2-({(3R)-3-[(3S)-1-(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl]-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl}oxy)acetamide
C23 H26 N4 O6 S
BIRTVLIYTDXUDJ-IFMALSPDSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
77Z PDBBind:  3HHK IC50: 6 (nM) from 1 assay(s)
Binding MOAD:  3HHK IC50: 6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.74α = 90
b = 107.442β = 90
c = 126.807γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

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: Advisory, Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Advisory, Refinement description
  • Version 1.3: 2024-02-21
    Changes: Advisory, Data collection, Database references, Derived calculations