7d5l
From Proteopedia
(Difference between revisions)
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==Discovery of BMS-986144, a Third Generation, Pan Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection== | ==Discovery of BMS-986144, a Third Generation, Pan Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection== | ||
| - | <StructureSection load='7d5l' size='340' side='right'caption='[[7d5l]]' scene=''> | + | <StructureSection load='7d5l' size='340' side='right'caption='[[7d5l]], [[Resolution|resolution]] 2.15Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D5L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7D5L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7d5l]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/9hepc 9hepc]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D5L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7D5L FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7d5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d5l OCA], [http://pdbe.org/7d5l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7d5l RCSB], [http://www.ebi.ac.uk/pdbsum/7d5l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7d5l ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GXO:[1,1,1-tris(fluoranyl)-2-methyl-propan-2-yl]+~{N}-[(1~{S},4~{R},6~{S},7~{Z},11~{R},13~{R},14~{S},18~{R})-13-ethyl-18-(7-fluoranyl-6-methoxy-isoquinolin-1-yl)oxy-11-methyl-4-[(1-methylcyclopropyl)sulfonylcarbamoyl]-2,15-bis(oxidanylidene)-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-en-14-yl]carbamate'>GXO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7d5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d5l OCA], [http://pdbe.org/7d5l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7d5l RCSB], [http://www.ebi.ac.uk/pdbsum/7d5l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7d5l ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype. | ||
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| + | Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.,Sun LQ, Mull E, D'Andrea S, Zheng B, Hiebert S, Gillis E, Bowsher M, Kandhasamy S, Baratam VR, Puttaswamy S, Pulicharla N, Vishwakrishnan S, Reddy S, Trivedi R, Sinha S, Sivaprasad S, Rao A, Desai S, Ghosh K, Anumula R, Kumar A, Rajamani R, Wang YK, Fang H, Mathur A, Rampulla R, Zvyaga TA, Mosure K, Jenkins S, Falk P, Tagore DM, Chen C, Rendunchintala K, Loy J, Meanwell NA, McPhee F, Scola PM J Med Chem. 2020 Dec 10;63(23):14740-14760. doi: 10.1021/acs.jmedchem.0c01296., Epub 2020 Nov 23. PMID:33226226<ref>PMID:33226226</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7d5l" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Anumula R]] | + | [[Category: Anumula, R]] |
| - | [[Category: Ghosh K]] | + | [[Category: Ghosh, K]] |
| - | [[Category: Kumar A]] | + | [[Category: Kumar, A]] |
| + | [[Category: Ns3/4a protease]] | ||
| + | [[Category: Viral protein]] | ||
Revision as of 11:07, 24 December 2020
Discovery of BMS-986144, a Third Generation, Pan Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
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