5J58

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1856)

5J58 の概要

• エントリーDOI: 10.2210/pdb5j58/pdb
• 分子名称: Methionyl-tRNA synthetase, putative, METHIONINE, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: synthetase, ligase, methionine, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 123732.05

構造登録者

Barros-Alvarez, X.,Hol, W.G.J. (登録日: 2016-04-01, 公開日: 2017-01-25, 最終更新日: 2024-03-06)

主引用文献

Huang, W.,Zhang, Z.,Barros-Alvarez, X.,Koh, C.Y.,Ranade, R.M.,Gillespie, J.R.,Creason, S.A.,Shibata, S.,Verlinde, C.L.,Hol, W.G.,Buckner, F.S.,Fan, E.
Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.
Eur J Med Chem, 124:1081-1092, 2016

PubMed Abstract: A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited ECs of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).

PubMed: 27788467
DOI: 10.1016/j.ejmech.2016.10.024

実験手法

X-RAY DIFFRACTION (2.8 Å)