[摘要]：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 similar to 1-10 mM binding affinity (K-D) were iteratively optimized to give leads with similar to 200 nM biochemical activity and low mu M cellular activity in a Replicon assay. (C) 2008 Elsevier Ltd. All rights reserved.
