文章基本信息

标题：Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking
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作者：Margherita Brindisi ; Simone Brogi ; Nicola Relitti 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：5
期号：1
DOI：10.1038/srep09705
语种：English
出版社：Springer Nature
摘要：Leishmaniasis is a neglected vector-born disease caused by a protozoan of the genus Leishmania and affecting more than 1.300.000 people worldwide. The couple tryparedoxin/tryparedoxin peroxidase is essential for parasite survival in the host since it neutralizes the hydrogen peroxide produced by macrophages during the infection. Herein we report a study aimed at discovering the first class of compounds able to non-covalently inhibit tryparedoxin peroxidase. We have solved the high-resolution structure of Tryparedoxin peroxidase I from Leishmania major (Lm TXNPx) in the reduced state and in fully folded conformation. A first series of compounds able to inhibit Lm TXNPx was identified by means of the high throughput docking technique. The inhibitory activity of these compounds was validated by a Horseradish peroxidase-based enzymatic assay and their affinity for Lm TXNPx calculated by surface plasmon resonance experiments. On the basis of these results, the analysis of the enzyme-inhibitor docked models allowed us to rationally design and synthesize a series of N , N -disubstituted 3-aminomethyl quinolones. These compounds showed an inhibitory potency against Lm TXNPx in the micromolar range. Among them, compound 12 represents the first non-covalent Lm TXNPx inhibitor reported to date and could pave the way to the discovery of a new class of drugs against leishmaniasis.