2FVC

Crystal structure of NS5B BK strain (delta 24) in complex with a 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.206 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

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

(2006) J Med Chem 49: 971-983

  • DOI: https://doi.org/10.1021/jm050855s
  • Primary Citation of Related Structures:  
    2FVC

  • PubMed Abstract: 

    Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.


  • Organizational Affiliation

    Department of Medicinal Chemistry and Drug Metabolism, the Musculoskeletal, Microbial and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA. Rosanna_2_Tedesco@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
polyprotein
A, B
563Hepatitis C virus subtype 1bMutation(s): 0 
Gene Names: NS5B
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
888
Query on 888

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-(1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-1-(3-methylbutyl)quinolin-2(1H)-one
C21 H21 N3 O4 S
MQFPIRFODWNQIO-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
888 Binding MOAD:  2FVC IC50: 32 (nM) from 1 assay(s)
PDBBind:  2FVC IC50: 32 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.5α = 90
b = 105.2β = 90
c = 126.4γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
MADNESSdata reduction
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-01-16
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Advisory, Refinement description
  • Version 1.4: 2023-08-30
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description