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

被引：64

作者：

Baiocco, Paola ^{[1
]}

Poce, Giovanna ^{[2
]}

Alfonso, Salvatore ^{[2
]}

Cocozza, Martina ^{[2
]}

Porretta, Giulio Cesare ^{[2
]}

Colotti, Gianni ^{[3
,4
]}

Biava, Mariangela ^{[2
]}

Moraca, Francesca ^{[5
]}

Botta, Maurizio ^{[5
]}

Yardley, Vanessa ^{[6
]}

Fiorillo, Annarita ^{[1
]}

Lantella, Antonella ^{[1
]}

Malatesta, Francesco ^{[1
]}

Ilari, Andrea ^{[3
,4
]}

机构：

[1] Univ Roma La Sapienza, Dipartimento Sci Biochim, I-00185 Rome, Italy

[2] Univ Roma La Sapienza, Ist Pasteur Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy

[3] Univ Roma La Sapienza, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy

[4] Univ Roma La Sapienza, Ist Biol & Patol Mol CNR, Dipartimento Sci Biochim, I-00185 Rome, Italy

[5] Univ Siena, Dipartimento Biochim Chim & Farm, I-53100 Siena, Italy

[6] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1E 7HT, England

来源：

CHEMMEDCHEM | 2013年 / 8卷 / 07期

关键词：

leishmania; medicinal chemistry; trypanothione reductase; X-ray crystallography; TRYPANOSOMA-CRUZI; ANTIMYCOBACTERIAL ACTIVITY; CRITHIDIA-FASCICULATA; GLUTATHIONE-REDUCTASE; CRYSTAL-STRUCTURE; DERIVATIVES; EXPRESSION; TOLUIDINE; DISCOVERY; COMPLEX;

D O I：

10.1002/cmdc.201300176

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1175 / 1183

页数：9

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