2YOJ

HCV NS5B polymerase complexed with pyridonylindole compound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Discovery of Sch 900188: A Potent Hepatitis C Virus Ns5B Polymerase Inhibitor Prodrug as a Development Candidate

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

(2014) ACS Med Chem Lett 5: 244

  • DOI: https://doi.org/10.1021/ml400192w
  • Primary Citation of Related Structures:  
    2YOJ

  • PubMed Abstract: 

    Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.


  • Organizational Affiliation

    Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE
A, B
585Hepacivirus hominisMutation(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
Binding Affinity Annotations 
IDSourceBinding Affinity
8Y6 Binding MOAD:  2YOJ IC50: 5 (nM) from 1 assay(s)
PDBBind:  2YOJ IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.271α = 90
b = 106.227β = 90
c = 134.553γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-09
    Type: Initial release
  • Version 1.1: 2014-06-18
    Changes: Database references
  • Version 1.2: 2017-08-23
    Changes: Data collection