National Center for
3CIZ: Crystal Structure Of Hepatitis C Virus Rna-Dependent Rna Polymerase Ns5b In Complex With Small Molecule Fragments
Bioorg. Med. Chem. Lett. (2008) 18 p.2990-2995
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 approximately 1-10mM binding affinity (K(D)) were iteratively optimized to give leads with approximately 200nM biochemical activity and low microM cellular activity in a Replicon assay.