6W49

Trypanosoma cruzi Malic Enzyme in complex with inhibitor (MEC010)

6W49 の概要

• エントリーDOI: 10.2210/pdb6w49/pdb
• 分子名称: Malic enzyme, CITRIC ACID, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, isomerase, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62413.21

構造登録者

Mercaldi, G.F.,Fagundes, M.,Faria, J.N.,Cordeiro, A.T. (登録日: 2020-03-10, 公開日: 2021-04-07, 最終更新日: 2023-10-18)

主引用文献

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

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: 34279922
DOI: 10.1021/acsinfecdis.1c00231

実験手法

X-RAY DIFFRACTION (1.7 Å)