3knx: Difference between revisions

Revision as of 12:27, 13 October 2021

HCV NS3 protease domain with P1-P3 macrocyclic ketoamide inhibitor

Structural highlights

3knx is a 4 chain structure with sequence from Hcv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	BME, JZT, ZN
Related:	3eyd
Gene:	NS3 (HCV)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease. J Med Chem. 2009 Jan 22;52(2):336-46. PMID:19102654 doi:10.1021/jm800940u

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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. Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease. J Med Chem. 2009 Jan 22;52(2):336-46. PMID:19102654 doi:10.1021/jm800940u

[1]

@@ Line 1: / Line 1: @@
 ==HCV NS3 protease domain with P1-P3 macrocyclic ketoamide inhibitor==
-<StructureSection load='3knx' size='340' side='right' caption='[[3knx]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+<StructureSection load='3knx' size='340' side='right'caption='[[3knx]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3knx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_(isolate_h77) Hepatitis c virus (isolate h77)]. 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>
+<table><tr><td colspan='2'>[[3knx]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hcv Hcv]. 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 [https://proteopedia.org/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>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eyd|3eyd]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3eyd|3eyd]]</div></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=63746 Hepatitis C virus (isolate H77)])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=63746 HCV])</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://pdbe.org/3knx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3knx RCSB], [http://www.ebi.ac.uk/pdbsum/3knx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3knx ProSAT]</span></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=3knx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3knx OCA], [https://pdbe.org/3knx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3knx RCSB], [https://www.ebi.ac.uk/pdbsum/3knx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3knx ProSAT]</span></td></tr>
 </table>
 <div style="background-color:#fffaf0;">
@@ Line 18: / Line 18: @@
 </div>
 <div class="pdbe-citations 3knx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Virus protease 3D structures|Virus protease 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Hcv]]
+[[Category: Large Structures]]
 [[Category: Agrawal, S]]
 [[Category: Blackman, M]]

3knx: Difference between revisions

Revision as of 12:27, 13 October 2021

HCV NS3 protease domain with P1-P3 macrocyclic ketoamide inhibitor

Structural highlights

Publication Abstract from PubMed

See Also

References

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