title: 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.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy [3] Dip. di Farmacia, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Relitti
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vallone
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Farmacia, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Istituto Pasteur Fondazione Cenci-Bolognetti and Istituto di Biologia e Patologia Molecolari IBPM- CNR, c/o Dipartimento di Scienze Biochimiche, Sapienza Università di Roma Piazzale A. Moro 5, 00185 Roma (Italy).
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.affiliation: Dipartimento di Scienze Biochimiche, Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Roma (Italy).
authors.forename: Gabriella
authors.initials: G
authors.lastname: Angiulli
authors.affiliation: Dipartimento di Scienze Biochimiche, Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Roma (Italy).
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Chiaro
authors.affiliation: Dipartimento di Scienze Biochimiche, Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Roma (Italy).
authors.forename: Annarita
authors.initials: A
authors.lastname: Fiorillo
authors.affiliation: Istituto Pasteur Fondazione Cenci-Bolognetti and Istituto di Biologia e Patologia Molecolari IBPM- CNR, c/o Dipartimento di Scienze Biochimiche, Sapienza Università di Roma Piazzale A. Moro 5, 00185 Roma (Italy).
authors.forename: Andrea
authors.initials: A
authors.lastname: Ilari
authors.affiliation: 1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D018320:Leishmania major / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010544:Peroxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D010544:Peroxidases; C110959:tryparedoxin peroxidase