3CO9

Crystal structure of HCV NS5B polymerase with a novel pyridazinone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.

Ruebsam, F.Webber, S.E.Tran, M.T.Tran, C.V.Murphy, D.E.Zhao, J.Dragovich, P.S.Kim, S.H.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.Sergeeva, M.V.Bartkowski, D.M.Nolan, T.G.Norris, D.A.Kirkovsky, L.

(2008) Bioorg Med Chem Lett 18: 3616-3621

  • DOI: https://doi.org/10.1016/j.bmcl.2008.04.066
  • Primary Citation of Related Structures:  
    3CO9

  • PubMed Abstract: 

    Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).


  • Organizational Affiliation

    Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. fruebsam@anadyspharma.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
578Hepatitis C virus (isolate BK)Mutation(s): 1 
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
3MS
Query on 3MS

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{3-[4-hydroxy-1-(3-methylbutyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7 -yl}methanesulfonamide
C20 H23 N5 O6 S2
FTVCONULIKITPZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3MS BindingDB:  3CO9 IC50: 10 (nM) from 1 assay(s)
EC50: 8.5 (nM) from 1 assay(s)
PDBBind:  3CO9 IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.701α = 90
b = 106.423β = 90
c = 126.431γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-02-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.3: 2024-02-21
    Changes: Data collection