4k1f | pdb_00004k1f
Crystal structure of reduced tryparedoxin peroxidase from leishmania major at 2.34 A resolution
Structural highlights
FunctionPublication Abstract from PubMedLeishmaniasis 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. Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking.,Brindisi M, Brogi S, Relitti N, Vallone A, Butini S, Gemma S, Novellino E, Colotti G, Angiulli G, Di Chiaro F, Fiorillo A, Ilari A, Campiani G Sci Rep. 2015 May 7;5:9705. doi: 10.1038/srep09705. PMID:25951439[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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