Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors

J Med Chem. 2003 Mar 27;46(7):1153-64. doi: 10.1021/jm020334u.

Abstract

Data from both our own and literature studies of the biochemistry and inhibition of influenza virus endonuclease was combined with data on the mechanism of action and the likely active site mechanism to propose a pharmacophore. The pharmacophore was used to design a novel structural class of inhibitors, some of which were found to have activities similar to that of known influenza endonuclease inhibitors and were also antiviral in cell culture.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Butyrates / chemical synthesis
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Cell Line
  • Combinatorial Chemistry Techniques
  • DNA-Directed RNA Polymerases / chemistry
  • Databases, Factual
  • Dogs
  • Endonucleases / antagonists & inhibitors*
  • Endonucleases / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Influenza A virus / drug effects
  • Influenza A virus / enzymology
  • Influenza B virus / drug effects
  • Influenza B virus / enzymology
  • Keto Acids / chemical synthesis
  • Keto Acids / chemistry
  • Keto Acids / pharmacology
  • Models, Molecular
  • Phthalimides / chemical synthesis
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Butyrates
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings
  • Keto Acids
  • Phthalimides
  • DNA-Directed RNA Polymerases
  • Endonucleases