A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase

J Med Chem. 2009 May 14;52(9):2667-72. doi: 10.1021/jm800455g.


Computational molecular docking provides an efficient and innovative approach to examine small molecule and protein interactions. We have utilized this method to identify potential inhibitors of the H5N1 neuraminidase protein. Of the 20 compounds tested, 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)propyl)amino)phenyl)-1-chloro-3-buten-2-one (1) (NSC89853) demonstrated the ability to inhibit viral replication at a level comparable to the known neuraminidase inhibitor oseltamivir. Compound 1 demonstrated efficacy across a number of cell-lines assays and in both the H1N1 and H5N1 viruses. The predicted binding of 1 to the known H5N1 neuraminidase structure indicates a binding interface largely nonoverlapping with that of oseltamivir or another neuraminidase inhibitor zanamivir. These results indicate that 1 or similar molecules would remain effective in the presence of virus mutations conferring resistance to either oseltamivir or zanamivir and also vice versa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Birds
  • Cell Line
  • Computational Biology
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H5N1 Subtype / drug effects*
  • Influenza A Virus, H5N1 Subtype / enzymology
  • Influenza in Birds / virology*
  • Models, Molecular*
  • Molecular Conformation
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Reproducibility of Results
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*


  • 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)propyl)amino)phenyl)-1-chloro-3-buten-2-one
  • Antiviral Agents
  • Pyrimidines
  • Small Molecule Libraries
  • Neuraminidase