2GC8

Structure of a Proline Sulfonamide Inhibitor Bound to HCV NS5b Polymerase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.216 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Proline Sulfonamides as Potent and Selective Hepatitis C Virus NS5b Polymerase Inhibitors. Evidence for a New NS5b Polymerase Binding Site.

Gopalsamy, A.Chopra, R.Lim, K.Ciszewski, G.Shi, M.Curran, K.J.Sukits, S.F.Svenson, K.Bard, J.Ellingboe, J.W.Agarwal, A.Krishnamurthy, G.Howe, A.Y.Orlowski, M.Feld, B.O'connell, J.Mansour, T.S.

(2006) J Med Chem 49: 3052-3055

  • DOI: https://doi.org/10.1021/jm060168g
  • Primary Citation of Related Structures:  
    2GC8

  • PubMed Abstract: 

    Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.


  • Organizational Affiliation

    Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. gopalsa@wyeth.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
578Hepacivirus hominisMutation(s): 1 
EC: 2.7.7.48
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
885
Query on 885

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-[(2-AMINO-4-CHLORO-5-METHYLPHENYL)SULFONYL]-L-PROLINE
C12 H15 Cl N2 O4 S
OWYKAFABUYXQLE-JTQLQIEISA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
885 Binding MOAD:  2GC8 IC50: 3100 (nM) from 1 assay(s)
PDBBind:  2GC8 IC50: 3100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.216 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.809α = 90
b = 105.91β = 90
c = 126.624γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2006-06-13
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description