3U4R

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

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
08F
Query on 08F
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		1-[(2-aminopyridin-4-yl)methyl]-5-chloro-N-({3-[(methylsulfonyl)amino]phenyl}sulfonyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide
C27 H23 Cl N6 O6 S2
CDTLONANIBXQJQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
08F Binding MOAD:  3U4R IC50: 39 (nM) from 1 assay(s)
PDBBind:  3U4R IC50: 39 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.922α = 90
b = 106.681β = 90
c = 134.317γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
autoBUSTERmodel building
BUSTERrefinement
CrystalCleardata reduction
CrystalCleardata scaling
autoBUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

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: 2024-02-28
    Changes: Data collection, Database references, Derived calculations