Inhibition of Leishmania infantum Trypanothione Reductase by Azole‐Based Compounds: a Comparative Analysis with Its Physiological Substrate by X‐ray Crystallography. Issue 7 (3rd June 2013)

• Record Type: Journal Article
• Authors: Baiocco, Paola; Poce, Giovanna; Alfonso, Salvatore; Cocozza, Martina; Porretta, Giulio Cesare; Colotti, Gianni; Biava, Mariangela; Moraca, Francesca; Botta, Maurizio; Yardley, Vanessa; Fiorillo, Annarita; Lantella, Antonella; Malatesta, Francesco; Ilari, Andrea
• Is Part Of: ChemMedChem. Volume 8:Issue 7(2013:Jul.)
• Page Start: 1175
• Page End: 1183
• Publication Date: 2013-06-03
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300176
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Herein we report a study aimed at discovering a new class of compounds that are able to inhibit <italic>Leishmania donovani</italic> 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)‐1<italic>H</italic>‐pyrrol‐3‐yl)methyl)thiomorpholine (compound <bold>1</bold>) as the most active. Enzymatic assays on <italic>Leishmania infantum</italic> trypanothione reductase (<italic>Li</italic>TR, belonging to the <italic>Leishmania donovani</italic> complex) shed light on both the interaction with, and the nature of inhibition by, compound <bold>1</bold>. 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 <italic>Li</italic>TR in complex with compound <bold>1</bold> confirmed all our results: compound <bold>1</bold> 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 <italic>Li</italic>TR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism.</p> </abstract>