6G83
Crystal structure of M. tuberculosis DprE1 in complex with sPBTZ169 (sulfonylPBTZ)
Summary for 6G83
| Entry DOI | 10.2210/pdb6g83/pdb |
| Related | 4NCR |
| Descriptor | Decaprenylphosphoryl-beta-D-ribose oxidase, FLAVIN-ADENINE DINUCLEOTIDE, [2-(4-cyclohexylsulfonylpiperazin-1-yl)-4-oxidanylidene-6-(trifluoromethyl)-1,3-benzothiazin-8-yl]-oxidanylidene-azanium, ... (4 entities in total) |
| Functional Keywords | dpre1, m. tuberculosis, inhibitor, complex, btz, oxidoreductase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 2 |
| Total formula weight | 107336.82 |
| Authors | Piton, J.,Makarov, V.,Cole, S.T. (deposition date: 2018-04-07, release date: 2018-08-01, Last modification date: 2025-10-01) |
| Primary citation | Piton, J.,Vocat, A.,Lupien, A.,Foo, C.S.,Riabova, O.,Makarov, V.,Cole, S.T. Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 62:-, 2018 Cited by PubMed Abstract: Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs. PubMed: 30012754DOI: 10.1128/AAC.00681-18 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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