3FRZ

Crystal Structure of HCV NS5B RNA polymerase in complex with PF868554


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor.

Li, H.Tatlock, J.Linton, A.Gonzalez, J.Jewell, T.Patel, L.Ludlum, S.Drowns, M.Rahavendran, S.V.Skor, H.Hunter, R.Shi, S.T.Herlihy, K.J.Parge, H.Hickey, M.Yu, X.Chau, F.Nonomiya, J.Lewis, C.

(2009) J Med Chem 52: 1255-1258

  • DOI: https://doi.org/10.1021/jm8014537
  • Primary Citation of Related Structures:  
    3FRZ

  • PubMed Abstract: 

    The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.


  • Organizational Affiliation

    Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. hui.li@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase576Hepatitis C virus (isolate BK)Mutation(s): 5 
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AG6
Query on AG6

Download Ideal Coordinates CCD File 
C [auth A]N-[(benzyloxy)carbonyl]-L-alpha-glutamyl-N-[(1S)-4-oxo-4-phenyl-1-propylbut-2-en-1-yl]-L-phenylalaninamide
C35 H39 N3 O7
LKWUEIKYVLZLJI-DTXPUJKBSA-N
AG0
Query on AG0

Download Ideal Coordinates CCD File 
B [auth A](6R)-6-cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one
C29 H37 N5 O3
SLVAPEZTBDBAPI-GDLZYMKVSA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
D [auth A]BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AG0 PDBBind:  3FRZ IC50: 7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.2α = 90
b = 83.2β = 90
c = 180.263γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
ARP/wARPmodel building
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-03-10 
  • Deposition Author(s): Parge, H.E.

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations