5VRL
CRYSTAL STRUCTURE OF THE INHA FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH AN12855, EBSI 4333.
Summary for 5VRL
| Entry DOI | 10.2210/pdb5vrl/pdb |
| Related | 5VRM 5VRN |
| Descriptor | Enoyl-[acyl-carrier-protein] reductase [NADH], (~{N}~{E})-~{N}-[[2-[[2-ethylsulfonyl-1,1-bis(oxidanyl)-3,4-dihydro-2,3,1$l^{4}-benzodiazaborinin-7-yl]oxy]-5-(trifluoromethyl)phenyl]methylidene]hydroxylamine (3 entities in total) |
| Functional Keywords | inha, enoyl-acyl reductase, tuberculosis, oxidoreductase |
| Biological source | Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh) |
| Total number of polymer chains | 1 |
| Total formula weight | 29297.27 |
| Authors | Abendroth, J.,Edwards, T.E.,Lorimer, D. (deposition date: 2017-05-11, release date: 2018-05-16, Last modification date: 2024-03-13) |
| Primary citation | Xia, Y.,Zhou, Y.,Carter, D.S.,McNeil, M.B.,Choi, W.,Halladay, J.,Berry, P.W.,Mao, W.,Hernandez, V.,O'Malley, T.,Korkegian, A.,Sunde, B.,Flint, L.,Woolhiser, L.K.,Scherman, M.S.,Gruppo, V.,Hastings, C.,Robertson, G.T.,Ioerger, T.R.,Sacchettini, J.,Tonge, P.J.,Lenaerts, A.J.,Parish, T.,Alley, M. Discovery of a cofactor-independent inhibitor ofMycobacterium tuberculosisInhA. Life Sci Alliance, 1:e201800025-e201800025, 2018 Cited by PubMed Abstract: New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of . The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents. PubMed: 30456352DOI: 10.26508/lsa.201800025 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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