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 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.

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…50 PA N endonuclease contains a dinuclear metal active site, with two Mn 2+ or Mg 2+ cations that promote endonuclease activity. 51 A functional RNA polymerase complex is essential to viral replication, 50 and the rst therapeutic targeting this protein, Baloxavir marboxil, has now gained FDA approval. 52 Baloxavir, along with other leading drug discovery efforts, have targeted the metal centers in the large active site of PA N as a means of enzyme inhibition.…”

“…5 and S17 †). 51,58 Considering the library as an entirety, a hit rate (percent inhibition > 50%) of approximately $40% was achieved against PA N and NDM-1, while Hsp90 had a hit rate of $15% (Fig. S16 †).…”

Size and Flexibility Define the Inhibition of the H3N2 Influenza Endonuclease Enzyme by Calix[n]arenes

“…The four other possible binding sites which would have no effect on the endonuclease inhibition have been removed. Figure 7B shows the interacting residues at the pharmacophore pocket as defined by Credille et al [39].…”

Aryl and Arylalkyl Substituted 3‐Hydroxypyridin‐2(1H)‐ones: Synthesis and Evaluation as Inhibitors of Influenza A Endonuclease

“…Structural studies on influenza A endonuclease and on the binding modes of various inhibitors of influenza virus PA endonuclease have been reported in recent years . Advances have also been made in understanding the structure–activity relationships associated with metal‐binding pharmacophores to influenza endonuclease . Evidence has also been provided to suggest that resistance against experimental endonuclease inhibitors, such as L‐742,001, can occur through specific mutations, highlighting this potential and concern in the development of clinical endonuclease inhibitors .…”

“…[7][8][9][10] Advances have also been made in understanding the structure-activity relationships associated with metal-binding pharmacophores to influenza endonuclease. [11] Evidence has also been provided to suggest that resistancea gainst experimental endonuclease inhibitors, such as L-742,001, can occur through specific mutations, highlighting this potentiala nd concern in the development of clinical endonuclease inhibitors. [12] Baloxavir marboxil (Xofluza)i sar ecently approved prodrug that targets the capsnatching endonuclease.…”