4TLR

NS5b in complex with lactam-thiophene carboxylic acids


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


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
NS5b578Hepatitis C virus (isolate 1)Mutation(s): 0 
EC: 2.7.7.48
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
33H
Query on 33H

Download Ideal Coordinates CCD File 
B [auth A]3-{(2R,5R)-5-cyclohexyl-2-[(2R)-2-hydroxypropyl]-3-oxomorpholin-4-yl}-5-(3,3-dimethylbut-1-yn-1-yl)thiophene-2-carboxylic acid
C24 H33 N O5 S
HBHITDKHOXLFLK-UIAACRFSSA-N
79Z
Query on 79Z

Download Ideal Coordinates CCD File 
C [auth A]5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide
C22 H23 F N2 O5 S
WTDWVLJJJOTABN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
33H Binding MOAD:  4TLR IC50: 3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.41α = 90
b = 68.06β = 90
c = 143.72γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
BUSTERrefinement
PDB_EXTRACTdata extraction
XSCALEdata scaling
Aimlessdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-12-10 
  • Deposition Author(s): Chopra, R.

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-10
    Type: Initial release
  • Version 1.1: 2015-02-04
    Changes: Derived calculations
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description, Source and taxonomy, Structure summary
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-12-27
    Changes: Data collection, Database references