4m3e

Rapid and efficient design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches

spinqualitylabelsall models 4m3e, resolution 2.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4m3e is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2B3 Related: 4m3b, 4m3d, 4m3f, 4m3g 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 Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed. Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches.,Villemagne B, Flipo M, Blondiaux N, Crauste C, Malaquin S, Leroux F, Piveteau C, Villeret V, Brodin P, Villoutreix BO, Sperandio O, Soror SH, Wohlkonig A, Wintjens R, Deprez B, Baulard AR, Willand N J Med Chem. 2014 Jun 12;57(11):4876-88. doi: 10.1021/jm500422b. Epub 2014 May 28. PMID:24818704 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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