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.
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.
Hendricks
Robert T
RT
Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Than.Hendricks@Roche.com
Fell
Jay B
JB
Blake
James F
JF
Fischer
John P
JP
Robinson
John E
JE
Spencer
Stacey R
SR
Stengel
Peter J
PJ
Bernacki
April L
AL
Leveque
Vincent J P
VJ
Le Pogam
Sophie
S
Rajyaguru
Sonal
S
Najera
Isabel
I
Josey
John A
JA
Harris
Jason R
JR
Swallow
Steven
S
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
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