4dw6

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

spinqualitylabelsall models 4dw6, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4dw6 is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0MN, GOL, NH4 Gene: etaR, ethR, MT3970, Rv3855 (Mycobacterium tuberculosis) Resources: FirstGlance, OCA, RCSB, PDBsum 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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