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| | ==Hepatitis C virus polymerase NS5B with saccharin inhibitor== | | ==Hepatitis C virus polymerase NS5B with saccharin inhibitor== |
| - | <StructureSection load='3h5s' size='340' side='right' caption='[[3h5s]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3h5s' size='340' side='right'caption='[[3h5s]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3h5s]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H5S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3H5S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3h5s]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_(isolate_BK) Hepatitis C virus (isolate BK)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H5S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H5S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H5S:(5S)-5-TERT-BUTYL-1-(4-FLUORO-3-METHYLBENZYL)-4-HYDROXY-3-[8-(METHYLSULFONYL)-1,1-DIOXIDO-6,7,8,9-TETRAHYDROISOTHIAZOLO[4,5-H]ISOQUINOLIN-3-YL]-1,5-DIHYDRO-2H-PYRROL-2-ONE'>H5S</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g86|3g86]], [[3h59|3h59]], [[2giq|2giq]], [[3h5u|3h5u]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H5S:(5S)-5-TERT-BUTYL-1-(4-FLUORO-3-METHYLBENZYL)-4-HYDROXY-3-[8-(METHYLSULFONYL)-1,1-DIOXIDO-6,7,8,9-TETRAHYDROISOTHIAZOLO[4,5-H]ISOQUINOLIN-3-YL]-1,5-DIHYDRO-2H-PYRROL-2-ONE'>H5S</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3h5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h5s OCA], [https://pdbe.org/3h5s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h5s RCSB], [https://www.ebi.ac.uk/pdbsum/3h5s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h5s ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3h5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h5s OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3h5s RCSB], [http://www.ebi.ac.uk/pdbsum/3h5s PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3h5s" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[RNA polymerase|RNA polymerase]] | + | *[[RNA polymerase 3D structures|RNA polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hepatitis c virus]] | + | [[Category: Large Structures]] |
| - | [[Category: RNA-directed RNA polymerase]]
| + | [[Category: Harris SF]] |
| - | [[Category: Harris, S F]] | + | [[Category: Wong A]] |
| - | [[Category: Wong, A]] | + | |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Capsid protein]]
| + | |
| - | [[Category: Cell membrane]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Envelope protein]]
| + | |
| - | [[Category: Fusion protein]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hcv]]
| + | |
| - | [[Category: Helicase]]
| + | |
| - | [[Category: Hepatitis]]
| + | |
| - | [[Category: Host-virus interaction]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Interferon antiviral system evasion]]
| + | |
| - | [[Category: Lipid droplet]]
| + | |
| - | [[Category: Lipoprotein]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Mitochondrion]]
| + | |
| - | [[Category: Multifunctional enzyme]]
| + | |
| - | [[Category: Ns5b]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Nucleotidyltransferase]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Oncogene]]
| + | |
| - | [[Category: Palmitate]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Ribonucleoprotein]]
| + | |
| - | [[Category: Rna replication]]
| + | |
| - | [[Category: Rna-binding]]
| + | |
| - | [[Category: Rna-directed rna polymerase]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| - | [[Category: Sh3-binding]]
| + | |
| - | [[Category: Thiol protease]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase rna-dependent rna polymerase]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Viral nucleoprotein]]
| + | |
| - | [[Category: Virion]]
| + | |
| Structural highlights
Publication Abstract from PubMed
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides.,de Vicente J, Hendricks RT, Smith DB, Fell JB, Fischer J, Spencer SR, Stengel PJ, Mohr P, Robinson JE, Blake JF, Hilgenkamp RK, Yee C, Adjabeng G, Elworthy TR, Li J, Wang B, Bamberg JT, Harris SF, Wong A, Leveque VJ, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, Farrell R Bioorg Med Chem Lett. 2009 Oct 1;19(19):5652-6. Epub 2009 Aug 8. PMID:19709881[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ de Vicente J, Hendricks RT, Smith DB, Fell JB, Fischer J, Spencer SR, Stengel PJ, Mohr P, Robinson JE, Blake JF, Hilgenkamp RK, Yee C, Adjabeng G, Elworthy TR, Li J, Wang B, Bamberg JT, Harris SF, Wong A, Leveque VJ, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, Farrell R. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5652-6. Epub 2009 Aug 8. PMID:19709881 doi:10.1016/j.bmcl.2009.08.022
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