6T98

Trypanothione Reductase from Leishmania infantum in complex with 9a

6T98 の概要

• エントリーDOI: 10.2210/pdb6t98/pdb
• 関連するPDBエントリー: 6T95 6T97
• 分子名称: Trypanothione reductase, 4-[3-methyl-1-[4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]-3-(2-piperidin-4-ylethoxy)phenyl]-1,2,3-triazol-3-ium-4-yl]butan-1-amine, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, oxidoreductase, leishmania, drug, flavoprotein
• 由来する生物種: Leishmania infantum
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55038.97

構造登録者

Carriles, A.A.,Hermoso, J.A. (登録日: 2019-10-26, 公開日: 2020-11-18, 最終更新日: 2024-11-13)

主引用文献

de Lucio, H.,Revuelto, A.,Carriles, A.A.,de Castro, S.,Garcia-Gonzalez, S.,Garcia-Soriano, J.C.,Alcon-Calderon, M.,Sanchez-Murcia, P.A.,Hermoso, J.A.,Gago, F.,Camarasa, M.J.,Jimenez-Ruiz, A.,Velazquez, S.
Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity.
Eur.J.Med.Chem., 244:114878-114878, 2022

PubMed Abstract: N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent inhibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time-dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low-molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.

PubMed: 36332553
DOI: 10.1016/j.ejmech.2022.114878

実験手法

X-RAY DIFFRACTION (3 Å)