3sfi

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.

spinqualitylabelsall models 3sfi, resolution 2.31Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: 3SF 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). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tetracycline repressor protein 3D structures

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