3D28

Crystal structure of hcv ns5b polymerase with a novel benzisothiazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.313 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.260 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.

Kim, S.H.Tran, M.T.Ruebsam, F.Xiang, A.X.Ayida, B.McGuire, H.Ellis, D.Blazel, J.Tran, C.V.Murphy, D.E.Webber, S.E.Zhou, Y.Shah, A.M.Tsan, M.Showalter, R.E.Patel, R.Gobbi, A.LeBrun, L.A.Bartkowski, D.M.Nolan, T.G.Norris, D.A.Sergeeva, M.V.Kirkovsky, L.Zhao, Q.Han, Q.Kissinger, C.R.

(2008) Bioorg Med Chem Lett 18: 4181-4185

  • DOI: https://doi.org/10.1016/j.bmcl.2008.05.083
  • Primary Citation of Related Structures:  
    3D28, 3D5M

  • PubMed Abstract: 

    A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.


  • Organizational Affiliation

    Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. sdsunhee@yahoo.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
B34
Query on B34

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(5S)-1-benzyl-3-(1,1-dioxido-1,2-benzisothiazol-3-yl)-4-hydroxy-5-(1-methylethyl)-1,5-dihydro-2H-pyrrol-2-one
C21 H20 N2 O4 S
XKOAFAIRGVAHRA-IBGZPJMESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B34 PDBBind:  3D28 IC50: 1400 (nM) from 1 assay(s)
Binding MOAD:  3D28 IC50: 1400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.313 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.260 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.979α = 90
b = 104.881β = 90
c = 126.008γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata collection
DENZOdata reduction
SCALEPACKdata 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: 2009-05-19
    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