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==Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.==
==Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.==
<StructureSection load='3sfi' size='340' side='right' caption='[[3sfi]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
<StructureSection load='3sfi' size='340' side='right'caption='[[3sfi]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3sfi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SFI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SFI FirstGlance]. <br>
<table><tr><td colspan='2'>[[3sfi]] 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=3SFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SFI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3SF:5,5,5-TRIFLUORO-1-{4-[3-(1,3-THIAZOL-2-YL)-1,2,4-OXADIAZOL-5-YL]PIPERIDIN-1-YL}PENTAN-1-ONE'>3SF</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]] 2.31&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3o8g|3o8g]], [[3o8h|3o8h]], [[3g1l|3g1l]], [[3g1m|3g1m]], [[1u9n|1u9n]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SF:5,5,5-TRIFLUORO-1-{4-[3-(1,3-THIAZOL-2-YL)-1,2,4-OXADIAZOL-5-YL]PIPERIDIN-1-YL}PENTAN-1-ONE'>3SF</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ethR, MT3970, RV3855 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=3sfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sfi OCA], [https://pdbe.org/3sfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sfi RCSB], [https://www.ebi.ac.uk/pdbsum/3sfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sfi ProSAT]</span></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=3sfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sfi OCA], [http://pdbe.org/3sfi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3sfi RCSB], [http://www.ebi.ac.uk/pdbsum/3sfi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3sfi 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 ==
Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore a second phase of optimization was required. Herein structure-property relationships study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906) which displays improved efficacy, in addition to high exposure of mice after oral administration.


Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.,Flipo M, Desroses M, Lecat-Guillet N, Villemagne B, Blondiaux N, Leroux F, Piveteau C, Mathys V, Flament MP, Siepmann J, Villeret V, Wohlkonig A, Wintjens R, Soror SH, Christophe T, Jeon HK, Locht C, Brodin P, Deprez BP, Baulard A, Willand N J Med Chem. 2011 Nov 20. PMID:22098589<ref>PMID:22098589</ref>
==See Also==
 
*[[Tetracycline repressor protein 3D structures|Tetracycline repressor protein 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3sfi" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Baulard, A R]]
[[Category: Large Structures]]
[[Category: Blondiaux, N]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Brodin, P]]
[[Category: Baulard AR]]
[[Category: Christophe, T]]
[[Category: Blondiaux N]]
[[Category: Desroses, M]]
[[Category: Brodin P]]
[[Category: Flament, M P]]
[[Category: Christophe T]]
[[Category: Flipo, M]]
[[Category: D prez B]]
[[Category: Jeon, H K]]
[[Category: Desroses M]]
[[Category: Lecat-Guillet, N]]
[[Category: Flament MP]]
[[Category: Leroux, F]]
[[Category: Flipo M]]
[[Category: Locht, C]]
[[Category: Jeon HK]]
[[Category: Mathys, V]]
[[Category: Lecat-Guillet N]]
[[Category: Piveteau, C]]
[[Category: Leroux F]]
[[Category: Siepmann, J]]
[[Category: Locht C]]
[[Category: Soror, S H]]
[[Category: Mathys V]]
[[Category: Villemagne, B]]
[[Category: Piveteau C]]
[[Category: Villeret, V]]
[[Category: Siepmann J]]
[[Category: Willand, N]]
[[Category: Soror SH]]
[[Category: Wintjens, R]]
[[Category: Villemagne B]]
[[Category: Wohlkonig, A]]
[[Category: Villeret V]]
[[Category: Prez, B D]]
[[Category: Willand N]]
[[Category: Dna]]
[[Category: Wintjens R]]
[[Category: Dna binding protein]]
[[Category: Wohlkonig A]]
[[Category: Inhibitor]]
[[Category: Tetr-family]]
[[Category: Transcription repressor-inhibitor complex]]
[[Category: Transcritptional regulatory repressor]]

Latest revision as of 12:55, 14 March 2024

Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.

3sfi, resolution 2.31Å

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