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

ABSTRACT: 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 PA_N 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 PA_N endonuclease, a class of highly active and selective fragments was developed that displays IC₅₀ values <50 nM. This SAR

SUBMITTER: Credille CV 

PROVIDER: S-EPMC6249039 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature