4MIB

Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.

Talamas, F.X.Abbot, S.C.Anand, S.Brameld, K.A.Carter, D.S.Chen, J.Davis, D.de Vicente, J.Fung, A.D.Gong, L.Harris, S.F.Inbar, P.Labadie, S.S.Lee, E.K.Lemoine, R.Le Pogam, S.Leveque, V.Li, J.McIntosh, J.Najera, I.Park, J.Railkar, A.Rajyaguru, S.Sangi, M.Schoenfeld, R.C.Staben, L.R.Tan, Y.Taygerly, J.P.Villasenor, A.G.Weller, P.E.

(2014) J Med Chem 57: 1914-1931

  • DOI: https://doi.org/10.1021/jm401329s
  • Primary Citation of Related Structures:  
    4MIA, 4MIB

  • PubMed Abstract: 

    In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.


  • Organizational Affiliation

    Pharma Research and Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE
A, B
570Hepatitis C virus (isolate BK)Mutation(s): 0 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
28M
Query on 28M

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide
C25 H32 N4 O4 S
QFGZCAFYEYRDGG-MRXNPFEDSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
C [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
28M Binding MOAD:  4MIB IC50: 0.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.413α = 90
b = 105.549β = 90
c = 126.006γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-05-07
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations