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3sfi

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Revision as of 12:10, 4 August 2016

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.

Structural highlights

3sfi is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3o8g, 3o8h, 3g1l, 3g1m, 1u9n
Gene:	ethR, MT3970, RV3855 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ETHR_MYCTU] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem. 2000 Sep 8;275(36):28326-31. PMID:10869356 doi:10.1074/jbc.M003744200
↑ DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. PMID:10944230
↑ 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. 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. J Med Chem. 2011 Nov 20. PMID:22098589 doi:10.1021/jm200825u

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3sfi"

@@ Line 1: / Line 1: @@
 ==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=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3sfi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Uncultured_bacterium_'eubacterium_sp.' Uncultured bacterium 'eubacterium sp.']. 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 [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>
 </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>
 <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='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=1733 uncultured bacterium 'eubacterium sp.'])</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'>[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://www.rcsb.org/pdb/explore.do?structureId=3sfi RCSB], [http://www.ebi.ac.uk/pdbsum/3sfi PDBsum]</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>
 == Function ==
@@ Line 18: / Line 19: @@
 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/>
 __TOC__
 </StructureSection>
-[[Category: Uncultured bacterium 'eubacterium sp.']]
 [[Category: Baulard, A R]]
 [[Category: Blondiaux, N]]

3sfi

From Proteopedia

Revision as of 12:10, 4 August 2016

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.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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