2xwy
From Proteopedia
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| - | [[ | + | ==STRUCTURE OF MK-3281, A POTENT NON-NUCLEOSIDE FINGER-LOOP INHIBITOR, IN COMPLEX WITH THE HEPATITIS C VIRUS NS5B POLYMERASE== |
| + | <StructureSection load='2xwy' size='340' side='right' caption='[[2xwy]], [[Resolution|resolution]] 2.53Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[2xwy]] is a 1 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=2XWY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XWY FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IB8:(7R)-14-CYCLOHEXYL-7-{[2-(DIMETHYLAMINO)ETHYL](METHYL)AMINO}-7,8-DIHYDRO-6H-INDOLO[1,2-E][1,5]BENZOXAZOCINE-11-CARBOXYLIC+ACID'>IB8</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nhu|1nhu]], [[2i1r|2i1r]], [[1jxp|1jxp]], [[2wcx|2wcx]], [[1gx6|1gx6]], [[2jc1|2jc1]], [[8ohm|8ohm]], [[1c2p|1c2p]], [[1a1q|1a1q]], [[1bt7|1bt7]], [[1cu1|1cu1]], [[2ax1|2ax1]], [[2jc0|2jc0]], [[1ns3|1ns3]], [[1nhv|1nhv]], [[1csj|1csj]], [[2who|2who]], [[2brl|2brl]], [[2brk|2brk]], [[1gx5|1gx5]], [[2ax0|2ax0]], [[2awz|2awz]], [[1quv|1quv]], [[1os5|1os5]]</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=2xwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xwy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xwy RCSB], [http://www.ebi.ac.uk/pdbsum/2xwy PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection. | ||
| - | { | + | Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase.,Narjes F, Crescenzi B, Ferrara M, Habermann J, Colarusso S, Ferreira Mdel R, Stansfield I, Mackay AC, Conte I, Ercolani C, Zaramella S, Palumbi MC, Meuleman P, Leroux-Roels G, Giuliano C, Fiore F, Di Marco S, Baiocco P, Koch U, Migliaccio G, Altamura S, Laufer R, De Francesco R, Rowley M J Med Chem. 2011 Jan 13;54(1):289-301. Epub 2010 Dec 8. PMID:21141896<ref>PMID:21141896</ref> |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
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==See Also== | ==See Also== | ||
*[[RNA polymerase|RNA polymerase]] | *[[RNA polymerase|RNA polymerase]] | ||
| - | + | == References == | |
| - | == | + | <references/> |
| - | < | + | __TOC__ |
| + | </StructureSection> | ||
[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: RNA-directed RNA polymerase]] | [[Category: RNA-directed RNA polymerase]] | ||
Revision as of 12:54, 22 October 2014
STRUCTURE OF MK-3281, A POTENT NON-NUCLEOSIDE FINGER-LOOP INHIBITOR, IN COMPLEX WITH THE HEPATITIS C VIRUS NS5B POLYMERASE
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