6HS0
EthR2 in complex with compound 5 (BDM71847)
Summary for 6HS0
| Entry DOI | 10.2210/pdb6hs0/pdb |
| Descriptor | Probable transcriptional regulatory protein, 1-[(3-chlorophenyl)methyl]piperazine (3 entities in total) |
| Functional Keywords | helix-turn-helix, tetr-family, complex, inhibitor, drug design, tuberculosis, ethionamide, dna binding protein |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 2 |
| Total formula weight | 48666.55 |
| Authors | Wintjens, R.,Wohlkonig, A.,Tanina, A. (deposition date: 2018-09-28, release date: 2019-02-27, Last modification date: 2024-01-24) |
| Primary citation | Prevet, H.,Moune, M.,Tanina, A.,Kemmer, C.,Herledan, A.,Frita, R.,Wohlkonig, A.,Bourotte, M.,Villemagne, B.,Leroux, F.,Gitzinger, M.,Baulard, A.R.,Deprez, B.,Wintjens, R.,Willand, N.,Flipo, M. A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2. Eur J Med Chem, 167:426-438, 2019 Cited by PubMed Abstract: 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. PubMed: 30784877DOI: 10.1016/j.ejmech.2019.02.023 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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