title: Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors.
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 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.
authors.affiliation: Medicinal Chemistry, SGX Pharmaceuticals, Inc., 10505 Roselle Street, San Diego, CA 92121, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Antonysamy
authors.forename: Brandon
authors.initials: B
authors.lastname: Aubol
authors.forename: Jeff
authors.initials: J
authors.lastname: Blaney
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Browner
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Normand
authors.initials: N
authors.lastname: Hébert
authors.forename: Jörg
authors.initials: J
authors.lastname: Hendle
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hopkins
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jefferson
authors.forename: Charles
authors.initials: C
authors.lastname: Kissinger
authors.forename: Vincent
authors.initials: V
authors.lastname: Leveque
authors.forename: David
authors.initials: D
authors.lastname: Marciano
authors.forename: Ethel
authors.initials: E
authors.lastname: McGee
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Brian
authors.initials: B
authors.lastname: Nolan
authors.forename: Masaki
authors.initials: M
authors.lastname: Tomimoto
authors.forename: Eduardo
authors.initials: E
authors.lastname: Torres
authors.forename: Tobi
authors.initials: T
authors.lastname: Wright
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D016174:Hepacivirus / Q000737:chemistry*; D006526:Hepatitis C / Q000201:enzymology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000502:physiology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase