6hs2

EthR2 in complex with compound 31 (BDM76150)

spinqualitylabelsall models 6hs2, resolution 1.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hs2 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.87Å Ligands: GNZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function O53623_MYCTU Publication Abstract from PubMed Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis. Very recently, we identified that inhibition of a transcriptional repressor, termed EthR2, derepresses a new bioactivation pathway that results in the boosting of ethionamide activation. Herein, we describe the identification of potent EthR2 inhibitors using fragment-based screening and structure-based optimization. A target-based screening of a fragment library using thermal shift assay followed by X-ray crystallography identified 5 hits. Rapid optimization of the tropinone chemical series led to compounds with improved in vitro potency. A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2.,Prevet H, Moune M, Tanina A, Kemmer C, Herledan A, Frita R, Wohlkonig A, Bourotte M, Villemagne B, Leroux F, Gitzinger M, Baulard AR, Deprez B, Wintjens R, Willand N, Flipo M Eur J Med Chem. 2019 Feb 10;167:426-438. doi: 10.1016/j.ejmech.2019.02.023. PMID:30784877 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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