Author/Authors :
Stephen S. Antonysamy، نويسنده , , Brandon Aubol، نويسنده , , Jeff Blaney، نويسنده , , Michelle F. Browner، نويسنده , , Anthony M. Giannetti، نويسنده , , Seth F. Harris، نويسنده , , Normand Hébert، نويسنده , , J?rg Hendle، نويسنده , , Stephanie Hopkins، نويسنده , , Elizabeth Jefferson، نويسنده , , Charles Kissinger، نويسنده , , Vincent Leveque، نويسنده , , David Marciano، نويسنده , , Ethel McGee، نويسنده , , Isabel N?jera، نويسنده , , Brian Nolan، نويسنده , , Masaki Tomimoto، نويسنده , , Eduardo Torres، نويسنده , , Tobi Wright، نويسنده ,
Abstract :
Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with 1–10 mM binding affinity (KD) were iteratively optimized to give leads with 200 nM biochemical activity and low μM cellular activity in a Replicon assay.
Keywords :
HCV , NS5B , Fragment screening , protein crystallography
