2fvc: Difference between revisions

Revision as of 04:20, 4 May 2008

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

OverviewOverview

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 StructureAbout this Structure

2FVC is a Single protein structure of sequence from Hepatitis c virus subtype 1b. Full crystallographic information is available from OCA.

ReferenceReference

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 Page seeded by OCA on Sun May 4 04:20:43 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:2fvc.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2fvc |SIZE=350|CAPTION= <scene name='initialview01'>2fvc</scene>, resolution 2.000&Aring;
+The line below this paragraph, containing "STRUCTURE_2fvc", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=888:3-(1,1-DIOXIDO-2H-1,2,4-BENZOTHIADIAZIN-3-YL)-4-HYDROXY-1-(3-METHYLBUTYL)-3,4-DIHYDROQUINOLIN-2(1H)-ONE'>888</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY=
+or leave the SCENE parameter empty for the default display.
-|GENE= NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31647 Hepatitis C virus subtype 1b])
+-->
-|DOMAIN=
+{{STRUCTURE_2fvc|  PDB=2fvc  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<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.ebi.ac.uk/pdbsum/2fvc PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2fvc RCSB]</span>
-}}
 '''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'''
@@ Line 28: / Line 25: @@
 [[Category: Singh, O.]]
 [[Category: Wonacott, A.]]
-[[Category: hcv polymerase]]
+[[Category: Hcv polymerase]]
-[[Category: thiadiazin inhibitor]]
+[[Category: Thiadiazin inhibitor]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 04:20:43 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:08:07 2008''