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

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 13, 2009, Pages 3637-3641

  Hendricks, Robert T ^b   Fell, Jay B ^a   Blake, James F ^a   Fischer, John P ^a   Robinson, John E ^a   Spencer, Stacey R ^a   Stengel, Peter J ^a   Bernacki, April L ^a   Leveque, Vincent J P ^b   Pogam, Sophie Le ^b   Rajyaguru, Sonal ^b   Najera, Isabel ^b   Josey, John A ^a   Harris, Jason R ^a   Swallow, Steven ^b  

^a ARRAY BIOPHARMA INC   (United States)

^b ROCHE BIOSCIENCE   (United States)

Author keywords

1,4 Benzothiazine; Anion; Computational; Conformation; gamess; HCV; Inhibitor; Non nucleoside; NS5b; Polymerase; Replicon

Indexed keywords

BENZOTHIADIAZINE DERIVATIVE; BENZOTHIAZINE DERIVATIVE; NON NUCLEOSIDE HEPATITIS C VIRUS NONSTRUCTURAL PROTEIN 5B POLYMERASE INHIBITOR; NONSTRUCTURAL PROTEIN 5B; NUCLEOTIDYLTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CALCULATION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HEPATITIS C VIRUS; HYDROGEN BOND; NONHUMAN; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANTIVIRAL AGENTS; BENZOTHIADIAZINES; COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; DNA-DIRECTED RNA POLYMERASES; ENZYME INHIBITORS; HEPACIVIRUS; HUMANS; PROTEIN BINDING; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZINES; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

HEPATITIS C VIRUS;

EID: 66349105264     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.119     Document Type: Article

References (22)

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9. During the course of our investigation, a related hydrogen bond analysis was published describing compounds 4 and 5. See Ref. 4b Herein, we describe an alternate synthesis of compound 4.
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18. PDB code: 2fvc.
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20. For comparison, the fully co-planar benzothiadiazine structure was found to be ca. 0.80 kcal/mol higher in energy than the boat form, and shown to be a transition state via computation of the analytical frequencies. A search of the CSD for thiadiazine containing molecules yields a number of relevant examples. In the majority of small molecule X-ray structures the thiadiazine fragment is largely planar, though subtle puckering is noted in a few examples. In light of the ab initio results, the planar conformation of the thiadiazine group is likely due to crystal packing effects. CSD, Version 5.13, April 1997 release. Entries CACTAZ0001, DIAZOX0001, JIFYUS0001, JIFZAZ0001, SEFMEV0001, SEFMIZ0001.
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