2fvc: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-[[Image:2fvc.jpg|left|200px]]<br /><applet load="2fvc" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2fvc, resolution 2.000&Aring;" />
-'''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'''<br />
-==Overview==
+==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==
-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.
+<StructureSection load='2fvc' size='340' side='right'caption='[[2fvc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2fvc]] is a 2 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=2FVC FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></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=2fvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fvc OCA], [https://pdbe.org/2fvc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fvc RCSB], [https://www.ebi.ac.uk/pdbsum/2fvc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fvc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q99AU2_9HEPC Q99AU2_9HEPC]
+== 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/main_output.php?pdb_ID=2fvc 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.
-==About this Structure==
+-(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>
-FVC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b] with <scene name='pdbligand=888:'>888</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FVC OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
--(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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16451063 16451063]
+</div>
-[[Category: Hepatitis c virus subtype 1b]]
+<div class="pdbe-citations 2fvc" style="background-color:#fffaf0;"></div>
-[[Category: Single protein]]
+== References ==
-[[Category: Concha, N.O.]]
+<references/>
-[[Category: Singh, O.]]
+__TOC__
-[[Category: Wonacott, A.]]
+</StructureSection>
-[[Category: 888]]
+[[Category: Hepatitis C virus subtype 1b]]
-[[Category: hcv polymerase]]
+[[Category: Large Structures]]
-[[Category: thiadiazin inhibitor]]
+[[Category: Concha NO]]
+[[Category: Singh O]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jan 29 19:45:25 2008''
+[[Category: Wonacott A]]