Case Studies – SSGCID

Center for Infectious Disease Research

SSGCID wanted to use fragment based screening to identify starting points for novel anti flu drugs.

SSGCID wanted to use fragment based screening to identify starting points for novel anti flu drugs.

EXPERIENCE/INSIGHT:

Beryllium performed fragment screening against the polymerase acidic (PA) subunit of the heterotrimeric PA-PB1-PB2 by STDNMR to identify fragments which bind to H1N1 PA-CTD and target a protein-protein interface:

Center for Infectious Disease HCV Study

  • Screened the Fragments of Life library consisting of 1080 compounds
  • 139 putative hits
  • Top 50 hits were examined in singleton experiments yielding 39 confirmed hits
  • 9 crystal structures of original and elaborated fragment hits

SOLUTION:

A number of fragments were identified by STD-NMR which were shown via x-ray crystallography to bind to a novel, distal yet highly conserved hydrophobic pocket on PA-CTD. One chemical series bound a novel, conserved (in flu A) hydrophobic surface binding site near the vRNA loading site. Although we expected many of the hits to bind to the PB1 binding site which is a hot spot for in silico binding and conformational change, we obtained a series of chlorophenyl compounds which bound to a surface site distal to the PB1 binding site. Interestingly, this site is located in close proximity to the viral RNA (vRNA) loading site and a species specific differential loop.

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