title: Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors.
abstract: A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA. hui.li@pfizer.com
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Tatlock
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Allen
authors.initials: A
authors.lastname: Borchardt
authors.forename: Peter
authors.initials: P
authors.lastname: Dragovich
authors.forename: Tanya
authors.initials: T
authors.lastname: Jewell
authors.forename: Tom
authors.initials: T
authors.lastname: Prins
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.forename: Julie
authors.initials: J
authors.lastname: Blazel
authors.forename: Hans
authors.initials: H
authors.lastname: Parge
authors.forename: Robert
authors.initials: R
authors.lastname: Love
authors.forename: Michael
authors.initials: M
authors.lastname: Hickey
authors.forename: Chau
authors.initials: C
authors.lastname: Doan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Shi
authors.forename: Rohit
authors.initials: R
authors.lastname: Duggal
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Shella
authors.initials: S
authors.lastname: Fuhrman
mesh_terms: D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006859:Hydrogen / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry
chemical_list: D011753:Pyrones; D017361:Viral Nonstructural Proteins; D006859:Hydrogen; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases