4NCM

Influenza polymerase basic protein 2 (PB2) bound to a small-molecule inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.82 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.

Clark, M.P., Ledeboer, M.W., Davies, I., Byrn, R.A., Jones, S.M., Perola, E., Tsai, A., Jacobs, M., Nti-Addae, K., Bandarage, U.K., Boyd, M.J., Bethiel, R.S., Court, J.J., Deng, H., Duffy, J.P., Dorsch, W.A., Farmer, L.J., Gao, H., Gu, W., Jackson, K., Jacobs, D.H., Kennedy, J.M., Ledford, B., Liang, J., Maltais, F., Murcko, M., Wang, T., Wannamaker, M.W., Bennett, H.B., Leeman, J.R., McNeil, C., Taylor, W.P., Memmott, C., Jiang, M., Rijnbrand, R., Bral, C., Germann, U., Nezami, A., Zhang, Y., Salituro, F.G., Bennani, Y.L., Charifson, P.S.

(2014) J Med Chem 57: 6668-6678

  • DOI: https://doi.org/10.1021/jm5007275
  • Primary Citation of Related Structures:  
    4NCE, 4NCM, 4P1U

  • PubMed Abstract: 

    In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

    • Organizational Affiliation: 

    Vertex Pharmaceuticals Inc. , 50 Northern Ave, Boston, Massachusetts 02210, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polymerase basic protein 2169Influenza A virus (A/Victoria/3/1975(H3N2))Mutation(s): 0 
Gene Names: PB2, polymerase basic protein 2 PB2
UniProt
Find proteins for P31345 (Influenza A virus (strain A/Victoria/3/1975 H3N2))
Explore P31345 
Go to UniProtKB:  P31345
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31345
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
704
Query on 704
Download Ideal Coordinates CCD File 
B [auth A]N~2~-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]-N,N-dimethyl-L-alaninamide
C16 H16 Cl F N6 O
RYLYZVYXGULJRD-QMMMGPOBSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
704 BindingDB:  4NCM Kd: 100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.82 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.1α = 90
b = 82.1β = 90
c = 54.36γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
globaldata reduction
globaldata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2014-07-30 
    • Deposition Author(s): Jacobs, M.D.

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-30
    Type: Initial release
  • Version 1.1: 2014-08-06
    Changes: Database references
  • Version 1.2: 2014-08-27
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description