Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography


Baiocco, P; Poce, G; Alfonso, S; Cocozza, M; Porretta, GC; Colotti, G; Biava, M; Moraca, F; Botta, M; Yardley, V; Fiorillo, A; Lantella, A; Malatesta, F; Ilari, A; (2013) Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography. ChemMedChem, 8 (7). pp. 1175-1183. ISSN 1860-7179 DOI: https://doi.org/10.1002/cmdc.201300176

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Abstract

Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in-house library of compounds in a whole-cell screening assay highlighted 4-((1-(4-ethylphenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1. A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X-ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism.

Item Type: Article
Keywords: leishmania, medicinal chemistry, trypanothione reductase, X-ray, crystallography, trypanosoma-cruzi, antimycobacterial activity, crithidia-fasciculata, glutathione-reductase, angstrom resolution, crystal-structure, derivatives, expression, toluidine, discovery
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Leishmaniasis Group
PubMed ID: 23733388
Web of Science ID: 320928400012
URI: http://researchonline.lshtm.ac.uk/id/eprint/1229494

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