3SKA

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


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
053
Query on 053

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
1-[(2-aminopyridin-4-yl)methyl]-3-(2-oxo-1,2-dihydropyridin-3-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid
C21 H15 F3 N4 O3
CNFSTRPHYZHTGV-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
053 Binding MOAD:  3SKA IC50: 17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.67α = 90
b = 106.97β = 90
c = 133.74γ = 90
Software Package:
Software NamePurpose
JDirectordata collection
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


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