Polyamine derivatives as trypanothione reductase inhibitors

MARÍA CRUZ MOLLO; LILIANA R. ORELLI

La Plata

Workshop; INTERNATIONAL WORKSHOP ON DRUG DESIGN AND NEGLECTED TROPICAL DISEASES; 2016

United Nations University y Universidad de La Plata

Polyamine derivatives as trypanothione reductase inhibitorsMaría C. Mollo, Liliana R. OrelliDepartamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de BuenosAires, CONICET. Junín 956, (1113) Buenos Aires, Argentina.PurposeChagas or American trypanosomiasis is a neglected disease caused by the protozoan parasite Trypanosoma cruzi. In South America it is endemic, affecting over 6 million people, and has spread over the United States, Canada and many other European countries.1a,b Trypanothione reductase is an enzyme that is essential in redox metabolic pathways for parasite survival. This enzyme therefore represents an interesting target for antitrypanosomal drug design. Trypanothione is the natural substrate of the enzyme and the spermidine motif present in its structure has been used to develop synthetic analogs as novel inhibitors.2 In this context, we propose the computational analysis of the interactions of novel selectively N-substituted polyamine derivatives with Trypanothione reductase.MethodologyUsing the crystallographic structures from Protein Data Bank and Autodock Vina, we study and explore the interaction of different polyamine derivatives with the active site of Trypanothione reductase.ResultsPreliminary docking studies with a few polyamine derivatives and related cyclic aminals shown a good affinity for the catalytic site of TR. Noteworthy, there is a good superposition with one of the most potent polyamine analog inhibitor reported, b.ConclusionsOn the basis of the results of the docking analysis, we will select the compounds with better affinity and score for their synthesis and biological evaluation as trypanocides.References1 (a) Drugs for Neglected Diseases initiative.Chagas Disease.http://www.dndi.org/diseases-projects/diseases/chagas.html; (b) OMS, La enfermedad de Chagas (tripanosomiasis americana), http://www.who.int/mediacentre/factsheets/fs340/es/2 (a) Colotti,G.; Baiocco,P.; Fiorillo, A.; Boffi,A.; Poser,E.; Di Chiaro,F.; Ilari A.; Future Med. Chem. 2013, 5(15), 1861?1875; (b) Krauth-Siegel,R.L.; Comini, M.A.; Bioch. Biophysica Acta 1780, 2008,1236?1248.3 Chitkul, B.; Bradley, M.;Bioorg. Med. Chem. Lett.,2000, 10, 2367-2369