3CDE

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: 0.228 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.

Li, L.S.Zhou, Y.Murphy, D.E.Stankovic, N.Zhao, J.Dragovich, P.S.Bertolini, T.Sun, Z.Ayida, B.Tran, C.V.Ruebsam, F.Webber, S.E.Shah, A.M.Tsan, M.Showalter, R.E.Patel, R.Lebrun, L.A.Bartkowski, D.M.Nolan, T.G.Norris, D.A.Kamran, R.Brooks, J.Sergeeva, M.V.Kirkovsky, L.Zhao, Q.Kissinger, C.R.

(2008) Bioorg Med Chem Lett 18: 3446-3455

  • DOI: https://doi.org/10.1016/j.bmcl.2008.02.072
  • Primary Citation of Related Structures:  
    3CDE

  • PubMed Abstract: 

    5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.


  • 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): 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
N3H
Query on N3H

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-1,2,4-benzothiadiazin-7-yl}methanesulfonamide
C21 H23 N5 O6 S3
UNKTYNIAIAATDF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
N3H BindingDB:  3CDE IC50: 10 (nM) from 1 assay(s)
EC50: 5 (nM) from 1 assay(s)
Binding MOAD:  3CDE IC50: 10 (nM) from 1 assay(s)
PDBBind:  3CDE IC50: 22 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.637α = 90
b = 106.258β = 90
c = 126.93γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection