Cyclic amide bioisosterism: strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.
Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.
Yang
Hanbiao
H
Medicinal Chemistry Department, Roche Palo Alto, LLC, Palo Alto, CA 94304, USA. Hanbiaoyang@gmail.com
Hendricks
Robert T
RT
Arora
Nidhi
N
Nitzan
Dov
D
Yee
Calvin
C
Lucas
Matthew C
MC
Yang
Yanli
Y
Fung
Amy
A
Rajyaguru
Sonal
S
Harris
Seth F
SF
Leveque
Vincent J P
VJ
Hang
Julie Q
JQ
Pogam
Sophie Le
SL
Reuter
Deborah
D
Tavares
Gisele A
GA
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase