2fvc: Difference between revisions
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[[Image: | ==Crystal structure of NS5B BK strain (delta 24) in complex with a 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinone== | ||
<StructureSection load='2fvc' size='340' side='right' caption='[[2fvc]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2fvc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FVC FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=888:3-(1,1-DIOXIDO-4H-1,2,4-BENZOTHIADIAZIN-3-YL)-4-HYDROXY-1-(3-METHYLBUTYL)QUINOLIN-2(1H)-ONE'>888</scene><br> | |||
<tr><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=31647 Hepatitis C virus subtype 1b])</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fvc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2fvc RCSB], [http://www.ebi.ac.uk/pdbsum/2fvc PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fv/2fvc_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluor o-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed. | |||
3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones , potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.,Tedesco R, Shaw AN, Bambal R, Chai D, Concha NO, Darcy MG, Dhanak D, Fitch DM, Gates A, Gerhardt WG, Halegoua DL, Han C, Hofmann GA, Johnston VK, Kaura AC, Liu N, Keenan RM, Lin-Goerke J, Sarisky RT, Wiggall KJ, Zimmerman MN, Duffy KJ J Med Chem. 2006 Feb 9;49(3):971-83. PMID:16451063<ref>PMID:16451063</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
< | |||
[[Category: Hepatitis c virus subtype 1b]] | [[Category: Hepatitis c virus subtype 1b]] | ||
[[Category: Concha, N O.]] | [[Category: Concha, N O.]] | ||
Revision as of 10:45, 30 September 2014
Crystal structure of NS5B BK strain (delta 24) in complex with a 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinoneCrystal structure of NS5B BK strain (delta 24) in complex with a 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinone
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRecently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluor o-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed. 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones , potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.,Tedesco R, Shaw AN, Bambal R, Chai D, Concha NO, Darcy MG, Dhanak D, Fitch DM, Gates A, Gerhardt WG, Halegoua DL, Han C, Hofmann GA, Johnston VK, Kaura AC, Liu N, Keenan RM, Lin-Goerke J, Sarisky RT, Wiggall KJ, Zimmerman MN, Duffy KJ J Med Chem. 2006 Feb 9;49(3):971-83. PMID:16451063[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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