3knx

<StructureSection load='3knx' size='340' side='right' caption='[[3knx]], [[Resolution|resolution]] 2.65&Aring;' scene=''>

<table><tr><td colspan='2'>[[3knx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KNX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KNX FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=JZT:(2R)-2-{(3S,13S,16AS,17AR,17BS)-13-[({(1S)-1-[(4,4-DIMETHYL-2,6-DIOXOPIPERIDIN-1-YL)METHYL]-2,2-DIMETHYLPROPYL}CARBAMOYL)AMINO]-17,17-DIMETHYL-1,14-DIOXOOCTADECAHYDRO-2H-CYCLOPROPA[3,4]PYRROLO[1,2-A][1,4]DIAZACYCLOHEXADECIN-3-YL}-2-HYDROXY-N-PROP-2-EN-1-YLETHANAMIDE'>JZT</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>

<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</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=3knx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3knx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3knx RCSB], [http://www.ebi.ac.uk/pdbsum/3knx PDBsum]</span></td></tr>

<div style="background-color:#fffaf0;">

== Publication Abstract from PubMed ==

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.

 

Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease.,Venkatraman S, Velazquez F, Wu W, Blackman M, Chen KX, Bogen S, Nair L, Tong X, Chase R, Hart A, Agrawal S, Pichardo J, Prongay A, Cheng KC, Girijavallabhan V, Piwinski J, Shih NY, Njoroge FG J Med Chem. 2009 Jan 22;52(2):336-46. PMID:19102654<ref>PMID:19102654</ref>

== References ==

[[Category: Hepatitis c virus subtype 1a]]

[[Category: Agrawal, S]]

[[Category: Blackman, M]]

[[Category: Bogen, S]]

[[Category: Chase, R]]

[[Category: Chen, K X]]

[[Category: Cheng, K C]]

[[Category: Girijavallabhan, V]]

[[Category: Hart, A]]

[[Category: Nair, L]]

[[Category: Njoroge, F G]]

[[Category: Pichardo, J]]

[[Category: Piwinski, J]]

[[Category: Prongay, A]]

[[Category: Shih, N Y]]

[[Category: Tong, X]]

[[Category: Velazquez, F]]

[[Category: Venkatraman, S]]

[[Category: Wu, W]]

[[Category: Viral protein]]