tetano
Editor, Senior Moderator
J Med Chem. 2018 Oct 16. doi: 10.1021/acs.jmedchem.8b01363. [Epub ahead of print]
[h=1]Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.[/h] Credille CV, Dick B, Morrison CN, Stokes RW, Adamek R, Wu NC, Wilson IA, Cohen SM.
[h=3]Abstract[/h] 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 optimizing the MBPs for PAN endonuclease, a class of highly active and selective fragments were developed that display 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.
PMID: 30351002 DOI: 10.1021/acs.jmedchem.8b01363
[h=1]Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.[/h] Credille CV, Dick B, Morrison CN, Stokes RW, Adamek R, Wu NC, Wilson IA, Cohen SM.
[h=3]Abstract[/h] 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 optimizing the MBPs for PAN endonuclease, a class of highly active and selective fragments were developed that display 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.
PMID: 30351002 DOI: 10.1021/acs.jmedchem.8b01363