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4dw6

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{{STRUCTURE_4dw6| PDB=4dw6 | SCENE= }}
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==Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.==
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===Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.===
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<StructureSection load='4dw6' size='340' side='right' caption='[[4dw6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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{{ABSTRACT_PUBMED_22738293}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4dw6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DW6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DW6 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MN:N-[4-(1,3-BENZOTHIAZOL-2-YL)PHENYL]-2-(3-METHOXYPHENOXY)ACETAMIDE'>0MN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">etaR, ethR, MT3970, Rv3855 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])</td></tr>
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<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=4dw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dw6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dw6 RCSB], [http://www.ebi.ac.uk/pdbsum/4dw6 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis -infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
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==Function==
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Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis.,Flipo M, Willand N, Lecat-Guillet N, Hounsou C, Desroses M, Leroux F, Lens Z, Villeret V, Wohlkonig A, Wintjens R, Christophe T, Kyoung Jeon H, Locht C, Brodin P, Baulard AR, Deprez B J Med Chem. 2012 Jul 26;55(14):6391-402. Epub 2012 Jul 17. PMID:22738293<ref>PMID:22738293</ref>
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[[http://www.uniprot.org/uniprot/ETHR_MYCTU ETHR_MYCTU]] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).<ref>PMID:10869356</ref> <ref>PMID:10944230</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4dw6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DW6 OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:022738293</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
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[[Category: Baulard, A R.]]
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[[Category: Baulard, A R]]
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[[Category: Brodin, P.]]
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[[Category: Brodin, P]]
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[[Category: Christophe, T.]]
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[[Category: Christophe, T]]
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[[Category: Deprez, B.]]
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[[Category: Deprez, B]]
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[[Category: Desroses, M.]]
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[[Category: Desroses, M]]
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[[Category: Flipo, M.]]
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[[Category: Flipo, M]]
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[[Category: Hounsou, C.]]
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[[Category: Hounsou, C]]
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[[Category: Jeon, H K.]]
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[[Category: Jeon, H K]]
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[[Category: Lecat-Guillet, N.]]
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[[Category: Lecat-Guillet, N]]
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[[Category: Lens, Z.]]
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[[Category: Lens, Z]]
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[[Category: Leroux, F.]]
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[[Category: Leroux, F]]
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[[Category: Locht, C.]]
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[[Category: Locht, C]]
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[[Category: Villeret, V.]]
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[[Category: Villeret, V]]
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[[Category: Willand, N.]]
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[[Category: Willand, N]]
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[[Category: Wintjens, R.]]
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[[Category: Wintjens, R]]
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[[Category: Wohlkonig, A.]]
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[[Category: Wohlkonig, A]]
[[Category: Dna binding protein]]
[[Category: Dna binding protein]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]

Revision as of 11:50, 21 December 2014

Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.

4dw6, resolution 2.00Å

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