5J5A

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 70786556)

Summary for 5J5A

• Entry DOI: 10.2210/pdb5j5a/pdb
• Descriptor: Methionyl-tRNA synthetase, putative, METHIONINE, [(3S)-3-(1H-benzimidazol-2-yl)piperidin-1-yl](2-methyl-1-benzofuran-5-yl)methanone, ... (4 entities in total)
• Functional Keywords: synthetase, ligase, methionine, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 123170.06

Authors

Barros-Alvarez, X.,Koh, C.Y.,Hol, W.G.J. (deposition date: 2016-04-01, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)