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==Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.==
==Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.==
<StructureSection load='4dw6' size='340' side='right' caption='[[4dw6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='4dw6' size='340' side='right'caption='[[4dw6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<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>
<table><tr><td colspan='2'>[[4dw6]] is a 1 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=4DW6 FirstGlance]. <br>
</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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
<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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
<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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dw6 OCA], [https://pdbe.org/4dw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dw6 RCSB], [https://www.ebi.ac.uk/pdbsum/4dw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dw6 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[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> 
[https://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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.
 
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>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Tetracycline repressor protein 3D structures|Tetracycline repressor protein 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Baulard, A R]]
[[Category: Baulard AR]]
[[Category: Brodin, P]]
[[Category: Brodin P]]
[[Category: Christophe, T]]
[[Category: Christophe T]]
[[Category: Deprez, B]]
[[Category: Deprez B]]
[[Category: Desroses, M]]
[[Category: Desroses M]]
[[Category: Flipo, M]]
[[Category: Flipo M]]
[[Category: Hounsou, C]]
[[Category: Hounsou C]]
[[Category: Jeon, H K]]
[[Category: Jeon HK]]
[[Category: Lecat-Guillet, N]]
[[Category: Lecat-Guillet N]]
[[Category: Lens, Z]]
[[Category: Lens Z]]
[[Category: Leroux, F]]
[[Category: Leroux F]]
[[Category: Locht, C]]
[[Category: Locht C]]
[[Category: Villeret, V]]
[[Category: Villeret V]]
[[Category: Willand, N]]
[[Category: Willand N]]
[[Category: Wintjens, R]]
[[Category: Wintjens R]]
[[Category: Wohlkonig, A]]
[[Category: Wohlkonig A]]
[[Category: Dna binding protein]]
[[Category: Inhibitor]]
[[Category: Tetr-family]]
[[Category: Transcription repressor-inhibitor complex]]
[[Category: Transcription-inhibitor complex]]
[[Category: Transcritptional regulatory repressor]]

Latest revision as of 10:58, 1 March 2024

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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