Identification of influenza PA-Nter endonuclease inhibitors using pharmacophore- and docking-based virtual screening

Bioorg Med Chem. 2018 Aug 15;26(15):4544-4550. doi: 10.1016/j.bmc.2018.07.046. Epub 2018 Jul 27.

Abstract

Searching for new antiviral agents, we focused our interest on the influenza PA-Nter endonuclease. Therefore, we developed a three-dimensional pharmacophore model which contains the binding features addressed to the metal-chelating active site. The obtained hypothesis has been fruitfully employed to select three "hit compounds" through an in silico screening campaign on our in-house database of small molecules. We studied the binding poses of these hit compounds using molecular docking, and subjected them to an enzymatic assay with recombinant PA-Nter endonuclease. Compound 20 proved the most active inhibitor of the endonucleolytic cleavage reaction, with an IC50 value of 12 μM.

Keywords: Endonuclease; Influenza virus; Molecular docking; Pharmacophore modeling; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Molecular Docking Simulation
  • Orthomyxoviridae / enzymology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • Viral Proteins
  • RNA-Dependent RNA Polymerase