6W57
Trypanosoma cruzi Malic Enzyme in complex with inhibitor (MEC069)
Summary for 6W57
| Entry DOI | 10.2210/pdb6w57/pdb |
| Descriptor | Malic enzyme, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ~{N}-[5-[[4-[bis(fluoranyl)methoxy]phenyl]sulfamoyl]-2-chloranyl-phenyl]-3,5-bis(fluoranyl)benzamide, ... (4 entities in total) |
| Functional Keywords | inhibitor, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Trypanosoma cruzi |
| Total number of polymer chains | 1 |
| Total formula weight | 62337.55 |
| Authors | Mercaldi, G.F.,Fagundes, M.,Faria, J.N.,Cordeiro, A.T. (deposition date: 2020-03-12, release date: 2021-04-07, Last modification date: 2023-10-18) |
| Primary citation | Mercaldi, G.F.,Eufrasio, A.G.,Ranzani, A.T.,do Nascimento Faria, J.,Mota, S.G.R.,Fagundes, M.,Bruder, M.,Cordeiro, A.T. Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box. Acs Infect Dis., 7:2455-2471, 2021 Cited by PubMed Abstract: Chagas disease, an infectious condition caused by , lacks treatment with drugs with desired efficacy and safety profiles. To address this unmet medical need, a set of trypanocidal compounds were identified through a large multicenter phenotypic-screening initiative and assembled in the GSK Chagas Box. In the present work, we report the screening of the Chagas Box against malic enzymes (MEs) and the identification of three potent inhibitors of its cytosolic isoform (TcMEc). One of these compounds, TCMDC-143108 (), came out as a nanomolar inhibitor of TcMEc, and 14 new derivatives were synthesized and tested for target inhibition and efficacy against the parasite. Moreover, we determined the crystallographic structures of TcMEc in complex with TCMDC-143108 () and six derivatives, revealing the allosteric inhibition site and the determinants of specificity. Our findings connect phenotypic hits from the Chagas Box to a relevant metabolic target in the parasite, providing data to foster new structure-activity guided hit optimization initiatives. PubMed: 34279922DOI: 10.1021/acsinfecdis.1c00231 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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