Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors.
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.
Antonysamy
Stephen S
SS
Medicinal Chemistry, SGX Pharmaceuticals, Inc., 10505 Roselle Street, San Diego, CA 92121, USA.
Aubol
Brandon
B
Blaney
Jeff
J
Browner
Michelle F
MF
Giannetti
Anthony M
AM
Harris
Seth F
SF
Hébert
Normand
N
Hendle
Jörg
J
Hopkins
Stephanie
S
Jefferson
Elizabeth
E
Kissinger
Charles
C
Leveque
Vincent
V
Marciano
David
D
McGee
Ethel
E
Nájera
Isabel
I
Nolan
Brian
B
Tomimoto
Masaki
M
Torres
Eduardo
E
Wright
Tobi
T
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
D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase