| Title: |
Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking |
| Authors: |
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. |
| Source: |
Scientific reports (Nature Publishing Group) 5 (2015). doi:10.1038/srep09705 ; info:cnr-pdr/source/autori: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./titolo:Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking/doi:10.1038srep09705/rivista:Scientific reports (Nature Publishing Group)/anno:2015/pagina_da:/pagina_a:/intervallo_pagine:/volume:5 |
| Publisher Information: |
Nature Publishing Group, London , Regno Unito |
| Publication Year: |
2015 |
| Collection: |
PUMAlab (ISTI CNR - Consiglio Nazionale delle Ricerche / National Research Council) |
| Subject Terms: |
GENETIC ALGORITHM; DYNAMICS; TRYPANOTHIONE; SURVIVAL; INSIGHTS; PATHWAY; DRUGS |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:cnr-pdr/author/matricola:1915/COLOTTI/GIANNI; info:cnr-pdr/author/matricola:5984/ILARI/ANDREA; http://www.cnr.it/prodotto/i/340593; https://publications.cnr.it/doc/340593; https://dx.doi.org/10.1038/srep09705; info:doi:10.1038/srep09705 |
| DOI: |
10.1038/srep09705 |
| Availability: |
http://www.cnr.it/prodotto/i/340593; https://publications.cnr.it/doc/340593; https://doi.org/10.1038/srep09705; http://www.scopus.com/inward/record.url?eid=2-s2.0-84929000082&partnerID=q2rCbXpz |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.DA1A2EC5 |
| Database: |
BASE |