3TYQ

SAR development and discovery of potent indole-based inhibitors of the hepatitis c virus NS5B polymerase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Novel Class of Highly Potent Irreversible Hepatitis C Virus NS5B Polymerase Inhibitors.

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

(2012) J Med Chem 55: 2089-2101

  • DOI: https://doi.org/10.1021/jm201322r
  • Primary Citation of Related Structures:  
    3TYQ

  • PubMed Abstract: 

    Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.


  • Organizational Affiliation

    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. kxcn@yahoo.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
576Hepatitis 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
Binding Affinity Annotations 
IDSourceBinding Affinity
HI4 PDBBind:  3TYQ IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.034α = 90
b = 106.863β = 90
c = 134.547γ = 90
Software Package:
Software NamePurpose
JDirectordata collection
BUSTER-TNTrefinement
HKL-2000data reduction
HKL-2000data scaling
BUSTER-TNTphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-01
    Type: Initial release
  • Version 1.1: 2012-03-21
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations