3CWJ

Crystal structure of hcv ns5b polymerase with a novel pyridazinone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.240 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase

Ellis, D.A.Blazel, J.K.Webber, S.E.Tran, C.V.Dragovich, P.S.Sun, Z.Ruebsam, F.McGuire, H.M.Xiang, A.X.Zhao, J.Li, L.S.Zhou, Y.Han, Q.Kissinger, C.R.Showalter, R.E.Lardy, M.Shah, A.M.Tsan, M.Patel, R.LeBrun, L.A.Kamran, R.Bartkowski, D.M.Nolan, T.G.Norris, D.A.Sergeeva, M.V.Kirkovsky, L.

(2008) Bioorg Med Chem Lett 18: 4628-4632

  • DOI: https://doi.org/10.1016/j.bmcl.2008.07.014
  • Primary Citation of Related Structures:  
    3CWJ

  • PubMed Abstract: 

    4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).


  • Organizational Affiliation

    Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE
A, B
578N/AMutation(s): 0 
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
321
Query on 321

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{3-[5-hydroxy-2-(3-methylbutyl)-3-oxo-6-thiophen-2-yl-2,3-dihydropyridazin-4-yl]-1,1-dioxido-2H-1,4-benzothiazin-7-yl}methanesulfonamide
C22 H24 N4 O6 S3
KLPXSYJOJCQFSY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
321 PDBBind:  3CWJ IC50: 10 (nM) from 1 assay(s)
Binding MOAD:  3CWJ IC50: 10 (nM) from 1 assay(s)
BindingDB:  3CWJ IC50: 10 (nM) from 1 assay(s)
EC50: min: 1.1, max: 11 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.240 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.107α = 90
b = 106.393β = 90
c = 126.731γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
EPMRphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-04-21
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance