Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking.

Abstract

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 (LmTXNPx) in the reduced state and in fully folded conformation. A first series of compounds able to inhibit LmTXNPx 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 LmTXNPx 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 LmTXNPx in the micromolar range. Among them, compound 12 represents the first non-covalent LmTXNPx inhibitor reported to date and could pave the way to the discovery of a new class of drugs against leishmaniasis.

• Authors: Margherita Brindisi, Simone Brogi, Nicola Relitti, Alessandra Vallone, Stefania Butini, Sandra Gemma, Ettore Novellino, Gianni Colotti, Gabriella Angiulli, Francesco Di Chiaro, Annarita Fiorillo, Andrea Ilari, Giuseppe Campiani
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 9705 (May 07 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 25951439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Enzyme Inhibitors
• Protozoan Proteins
• Peroxidases
• tryparedoxin peroxidase

Topics

• Antiprotozoal Agents (chemistry, pharmacology)
• Binding Sites
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemistry, pharmacology)
• Leishmania major (drug effects, enzymology)
• Models, Molecular
• Molecular Conformation
• Molecular Docking Simulation
• Peroxidases (antagonists & inhibitors, chemistry)
• Protein Binding
• Protozoan Proteins (antagonists & inhibitors, chemistry)
• Quantitative Structure-Activity Relationship
• Surface Plasmon Resonance