Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease

J Med Chem. 2018 Nov 21;61(22):10206-10217. doi: 10.1021/acs.jmedchem.8b01363. Epub 2018 Oct 31.


Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values <50 nM. This SAR led to structurally distinct molecules that also displayed IC50 values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • DNA-Directed RNA Polymerases / chemistry
  • DNA-Directed RNA Polymerases / metabolism
  • Drug Discovery
  • Endonucleases / antagonists & inhibitors*
  • Endonucleases / chemistry
  • Endonucleases / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Influenza A Virus, H1N1 Subtype / enzymology*
  • Inhibitory Concentration 50
  • Metals / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Metals
  • DNA-Directed RNA Polymerases
  • Endonucleases