3SKE

I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.

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

(2011) Bioorg Med Chem Lett 21: 5336-5341

  • DOI: https://doi.org/10.1016/j.bmcl.2011.07.021
  • Primary Citation of Related Structures:  
    3SKA, 3SKE, 3SKH

  • PubMed Abstract: 

    SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and 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
HCV NS5B RNA_DEPENDENT RNA POLYMERASE
A, B
576Hepatitis C virus isolate HC-J4Mutation(s): 0 
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
054
Query on 054

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
1-[(2-aminopyridin-4-yl)methyl]-3-(2,4-dioxo-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid
C22 H14 F3 N5 O4 S
DKKCMDSCGHLOLY-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
054 Binding MOAD:  3SKE IC50: 32 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.7α = 90
b = 107.26β = 90
c = 134.22γ = 90
Software Package:
Software NamePurpose
JDirectordata collection
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-31
    Type: Initial release
  • Version 1.1: 2012-09-26
    Changes: Database references