4KHM

HCV NS5B GT1A with GSK5852


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase.

Maynard, A.Crosby, R.M.Ellis, B.Hamatake, R.Hong, Z.Johns, B.A.Kahler, K.M.Koble, C.Leivers, A.Leivers, M.R.Mathis, A.Peat, A.J.Pouliot, J.J.Roberts, C.D.Samano, V.Schmidt, R.M.Smith, G.K.Spaltenstein, A.Stewart, E.L.Thommes, P.Turner, E.M.Voitenleitner, C.Walker, J.T.Waitt, G.Weatherhead, J.Weaver, K.Williams, S.Wright, L.Xiong, Z.Z.Haigh, D.Shotwell, J.B.

(2014) J Med Chem 57: 1902-1913

  • DOI: https://doi.org/10.1021/jm400317w
  • Primary Citation of Related Structures:  
    4KAI, 4KB7, 4KBI, 4KE5, 4KHM, 4KHR

  • PubMed Abstract: 

    A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.


  • Organizational Affiliation

    GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HCV Polymerase
A, B
579hepatitis C virus genotype 1aMutation(s): 7 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for B1PPP0 (hepatitis C virus genotype 1a)
Explore B1PPP0 
Go to UniProtKB:  B1PPP0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupB1PPP0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1PV
Query on 1PV

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
[4-({[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1-benzofuran-6-yl](methylsulfonyl)amino}methyl)-2-fluorophenyl]boronic acid
C27 H25 B F2 N2 O6 S
GDSKPIAEYNJODX-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
G [auth B]
H [auth B]
I [auth B]
D [auth A],
E [auth A],
G [auth B],
H [auth B],
I [auth B],
J [auth B],
K [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.03α = 89.63
b = 61.111β = 87.06
c = 91.682γ = 80.91
Software Package:
Software NamePurpose
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-15
    Type: Initial release
  • Version 1.1: 2013-05-29
    Changes: Database references
  • Version 1.2: 2014-03-26
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations
  • Version 1.4: 2024-03-13
    Changes: Source and taxonomy, Structure summary