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

Cy V. Credille, Benjamin L. Dick, Christine N. Morrison, Ryjul W. Stokes, Rebecca N. Adamek, Nicholas C. Wu, Ian A. Wilson, Seth M. Cohen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)10206-10217
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number22
StatePublished - Nov 21 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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