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==Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors== | ==Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors== | ||
<StructureSection load='4xir' size='340' side='right' caption='[[4xir]], [[Resolution|resolution]] 1.70Å' scene=''> | <StructureSection load='4xir' size='340' side='right'caption='[[4xir]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xir]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XIR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XIR FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xir]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XIR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XIR FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40X:(6S)-2-CHLORO-8,11,11-TRIMETHYL-9-OXO-6-PROPYL-6,7,9,10,11,12-HEXAHYDROINDOLO[2,1-D][1,5]BENZOXAZEPINE-3-CARBOXAMIDE'>40X</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40X:(6S)-2-CHLORO-8,11,11-TRIMETHYL-9-OXO-6-PROPYL-6,7,9,10,11,12-HEXAHYDROINDOLO[2,1-D][1,5]BENZOXAZEPINE-3-CARBOXAMIDE'>40X</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xip|4xip]], [[4xiq|4xiq]], [[4xit|4xit]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xip|4xip]], [[4xiq|4xiq]], [[4xit|4xit]]</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=4xir FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xir OCA], [http://pdbe.org/4xir PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xir RCSB], [http://www.ebi.ac.uk/pdbsum/4xir PDBsum]</span></td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4xir FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xir OCA], [http://pdbe.org/4xir PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xir RCSB], [http://www.ebi.ac.uk/pdbsum/4xir PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xir ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
| Line 26: | Line 27: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Neubert, T]] | [[Category: Neubert, T]] | ||
[[Category: Zuccola, H J]] | [[Category: Zuccola, H J]] | ||
[[Category: Chaperone-chaperone inhibitor complex]] | [[Category: Chaperone-chaperone inhibitor complex]] | ||
Revision as of 10:16, 29 May 2019
Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitorsDiscovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedTwo novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30). Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.,Neubert T, Numa M, Ernst J, Clemens J, Krenitsky P, Liu M, Fleck B, Woody L, Zuccola H, Stamos D Bioorg Med Chem Lett. 2015 Mar 15;25(6):1338-42. doi: 10.1016/j.bmcl.2015.01.023., Epub 2015 Jan 20. PMID:25677667[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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