3U4O

Novel HCV NS5B polymerase Inhibitors: Discovery of Indole C2 Acyl sulfonamides


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

II. Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 acyl sulfonamides.

Anilkumar, G.N.Selyutin, O.Rosenblum, S.B.Zeng, Q.Jiang, Y.Chan, T.Y.Pu, H.Wang, L.Bennett, F.Chen, K.X.Lesburg, C.A.Duca, J.Gavalas, S.Huang, Y.Pinto, P.Sannigrahi, M.Velazquez, F.Venkatraman, S.Vibulbhan, B.Agrawal, S.Ferrari, E.Jiang, C.K.Huang, H.C.Shih, N.Y.George Njoroge, F.Kozlowski, J.A.

(2012) Bioorg Med Chem Lett 22: 713-717

  • DOI: https://doi.org/10.1016/j.bmcl.2011.10.041
  • Primary Citation of Related Structures:  
    3U4O, 3U4R

  • PubMed Abstract: 

    Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity.


  • Organizational Affiliation

    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. gopinadhan.anilkumar@Merck.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 HC-J4Mutation(s): 0 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for O92972 (Hepatitis C virus genotype 1b (strain HC-J4))
Explore O92972 
Go to UniProtKB:  O92972
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO92972
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
08E
Query on 08E

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
1-[(2-aminopyridin-4-yl)methyl]-5-chloro-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxylic acid
C20 H15 Cl N4 O3
XPHRQEMVNFKEIN-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
D [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
08E PDBBind:  3U4O IC50: 53 (nM) from 1 assay(s)
Binding MOAD:  3U4O IC50: 53 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.76α = 90
b = 106.79β = 90
c = 133.82γ = 90
Software Package:
Software NamePurpose
JDirectordata collection
autoBUSTERmodel building
BUSTERrefinement
autoPROCdata scaling
SCALAdata scaling
autoBUSTERphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-12-07
    Type: Initial release
  • Version 1.1: 2012-01-11
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description