title: Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: Synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors.
abstract: The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.
authors.affiliation: Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Than.Hendricks@Roche.com
authors.forename: Robert T
authors.initials: RT
authors.lastname: Hendricks
authors.forename: Jay B
authors.initials: JB
authors.lastname: Fell
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: John P
authors.initials: JP
authors.lastname: Fischer
authors.forename: John E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Spencer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stengel
authors.forename: April L
authors.initials: AL
authors.lastname: Bernacki
authors.forename: Vincent J P
authors.initials: VJ
authors.lastname: Leveque
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.forename: Jason R
authors.initials: JR
authors.lastname: Harris
authors.forename: Steven
authors.initials: S
authors.lastname: Swallow
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C446962:1,4-benzothiazine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase