4EO8

HCV NS5B polymerase inhibitors: Tri-substituted acylhydrazines as tertiary amide bioisosteres

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history. 


Literature

Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.

Canales, E., Carlson, J.S., Appleby, T., Fenaux, M., Lee, J., Tian, Y., Tirunagari, N., Wong, M., Watkins, W.J.

(2012) Bioorg Med Chem Lett 22: 4288-4292

  • DOI: https://doi.org/10.1016/j.bmcl.2012.05.025
  • Primary Citation of Related Structures:  
    4EO6, 4EO8

  • PubMed Abstract: 

    The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency.

    • Organizational Affiliation: 

    Medicinal Chemistry Department, Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404, United States. eda.canales@gilead.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
577Hepatitis C virus (isolate BK)Mutation(s): 3 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for P26663 (Hepatitis C virus genotype 1b (isolate BK))
Explore P26663 
Go to UniProtKB:  P26663
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26663
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0S3
Query on 0S3
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		5-(3,3-dimethylbut-1-yn-1-yl)-3-{2,2-dimethyl-1-[(trans-4-methylcyclohexyl)carbonyl]hydrazinyl}thiophene-2-carboxylic acid
C21 H30 N2 O3 S
LATMUSXHHVOIII-SHTZXODSSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0S3 Binding MOAD:  4EO8 Kd: 7 (nM) from 1 assay(s)
PDBBind:  4EO8 Kd: 7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.59α = 90
b = 105.93β = 90
c = 126.72γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
BOSdata collection
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-27
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description