4TN2

NS5b in complex with lactam-thiophene carboxylic acids


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors.

Barnes-Seeman, D.Boiselle, C.Capacci-Daniel, C.Chopra, R.Hoffmaster, K.Jones, C.T.Kato, M.Lin, K.Ma, S.Pan, G.Shu, L.Wang, J.Whiteman, L.Xu, M.Zheng, R.Fu, J.

(2014) Bioorg Med Chem Lett 24: 3979-3985

  • DOI: https://doi.org/10.1016/j.bmcl.2014.06.031
  • Primary Citation of Related Structures:  
    4TLR, 4TN2

  • PubMed Abstract: 

    Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.


  • Organizational Affiliation

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Genome polyprotein577Hepatitis B virusMutation(s): 0 
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
33J
Query on 33J

Download Ideal Coordinates CCD File 
B [auth A]3-[(2R)-2-cyclohexyl-5-oxopyrrolidin-1-yl]-5-phenylthiophene-2-carboxylic acid
C21 H23 N O3 S
XKVVNTKSBNWRDA-MRXNPFEDSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 159.191α = 90
b = 159.191β = 90
c = 71.226γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement
XSCALEdata scaling
Aimlessdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2014-09-17 
  • Deposition Author(s): Chopra, R.

Revision History  (Full details and data files)

  • Version 1.0: 2014-09-17
    Type: Initial release
  • Version 1.1: 2015-02-04
    Changes: Derived calculations
  • Version 1.2: 2016-06-01
    Changes: Data collection
  • Version 1.3: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.4: 2023-12-27
    Changes: Data collection, Database references