5NFH

Trypanosoma brucei methionyl-tRNA synthetase in complex with a quinazolinone inhibitor

5NFH の概要

• エントリーDOI: 10.2210/pdb5nfh/pdb
• 分子名称: Methionyl-tRNA synthetase, putative, GLYCEROL, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: synthetase, ligase, methionine, inhibitor, ligase-ligase inhibitor, complex, drug discovery
• 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: 122598.45

構造登録者

Robinson, D.A.,Eadsforth, T.C.,Shepherd, S.M.,Torrie, L.S.,De Rycker, M.,Gilbert, I.H. (登録日: 2017-03-14, 公開日: 2017-10-11, 最終更新日: 2024-01-17)

主引用文献

Torrie, L.S.,Brand, S.,Robinson, D.A.,Ko, E.J.,Stojanovski, L.,Simeons, F.R.C.,Wyllie, S.,Thomas, J.,Ellis, L.,Osuna-Cabello, M.,Epemolu, O.,Nuhs, A.,Riley, J.,MacLean, L.,Manthri, S.,Read, K.D.,Gilbert, I.H.,Fairlamb, A.H.,De Rycker, M.
Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.
ACS Infect Dis, 3:718-727, 2017

PubMed Abstract: Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (K of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.

PubMed: 28967262
DOI: 10.1021/acsinfecdis.7b00047

実験手法

X-RAY DIFFRACTION (2.8 Å)