4ZT6

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor N-[(4R)-6,8-dichloro-3,4-dihydro-2H-chromen-4-yl]-N'-(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1709)

Summary for 4ZT6

• Entry DOI: 10.2210/pdb4zt6/pdb
• Related: 4ZT2 4ZT3 4ZT4 4ZT5 4ZT7
• Descriptor: Methionyl-tRNA synthetase, METHIONINE, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: ligase, aminoacyl-trna synthetase, aars, metrs, trypanosoma brucei, protein-inhibitor complex, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 123741.43

Authors

Koh, C.-Y.,Hol, W.G.J. (deposition date: 2015-05-14, release date: 2016-05-04, Last modification date: 2024-11-06)

Primary citation

Zhang, Z.,Koh, C.Y.,Ranade, R.M.,Shibata, S.,Gillespie, J.R.,Hulverson, M.A.,Huang, W.,Nguyen, J.,Pendem, N.,Gelb, M.H.,Verlinde, C.L.,Hol, W.G.,Buckner, F.S.,Fan, E.
5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.
Acs Infect Dis., 2:399-404, 2016

PubMed Abstract: Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.

PubMed: 27627628
DOI: 10.1021/acsinfecdis.6b00036

Experimental method

X-RAY DIFFRACTION (2.25 Å)