6T98

Trypanothione Reductase from Leishmania infantum in complex with 9a

Summary for 6T98

• Entry DOI: 10.2210/pdb6t98/pdb
• Related: 6T95 6T97
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, oxidoreductase, leishmania, drug, flavoprotein
• Biological source: Leishmania infantum
• Total number of polymer chains: 1
• Total formula weight: 55038.97

Authors

Carriles, A.A.,Hermoso, J.A. (deposition date: 2019-10-26, release date: 2020-11-18, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)