4nwl
From Proteopedia
(Difference between revisions)
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| - | + | ==Crystal structure of hepatis c virus protease (ns3) complexed with bms-650032 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-4-((7-chloro-4-methoxy-1-isoquinolinyl)o xy)-n-((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylc yclopropyl)-l-prolinamide== | |
| - | + | <StructureSection load='4nwl' size='340' side='right' caption='[[4nwl]], [[Resolution|resolution]] 2.20Å' scene=''> | |
| - | { | + | == Structural highlights == |
| + | <table><tr><td colspan='2'>[[4nwl]] is a 2 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=4NWL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NWL FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2R9:N-(TERT-BUTOXYCARBONYL)-3-METHYL-L-VALYL-(4R)-4-[(7-CHLORO-4-METHOXYISOQUINOLIN-1-YL)OXY]-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-L-PROLINAMIDE'>2R9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nwk|4nwk]]</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=4nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nwl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nwl RCSB], [http://www.ebi.ac.uk/pdbsum/4nwl PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients. | ||
| - | + | Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.,Scola PM, Wang AX, Good AC, Sun LQ, Combrink KD, Campbell JA, Chen J, Tu Y, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea S, Zheng B, Hewawasam P, Ding M, Thuring J, Li J, Hernandez D, Yu F, Falk P, Zhai G, Sheaffer AK, Chen C, Lee MS, Barry D, Knipe JO, Li W, Han YH, Jenkins S, Gesenberg C, Gao Q, Sinz MW, Santone KS, Zvyaga T, Rajamani R, Klei HE, Colonno RJ, Grasela DM, Hughes E, Chien C, Adams S, Levesque PC, Li D, Zhu J, Meanwell NA, McPhee F J Med Chem. 2014 Mar 13;57(5):1708-29. doi: 10.1021/jm401840s. Epub 2014 Feb 20. PMID:24555570<ref>PMID:24555570</ref> | |
| - | + | ||
| - | == | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | + | </div> | |
| - | [[Category: Klei, H E | + | == References == |
| - | [[Category: Muckelbauer, J K | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Hepatitis c virus subtype 1a]] | ||
| + | [[Category: Klei, H E]] | ||
| + | [[Category: Muckelbauer, J K]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Hydrolase/hydrolase inhibitor]] | [[Category: Hydrolase/hydrolase inhibitor]] | ||
[[Category: Serine protease]] | [[Category: Serine protease]] | ||
Revision as of 09:02, 5 January 2015
Crystal structure of hepatis c virus protease (ns3) complexed with bms-650032 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-4-((7-chloro-4-methoxy-1-isoquinolinyl)o xy)-n-((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylc yclopropyl)-l-prolinamide
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