Application of Computer-Aided Drug Repurposing in the Search of New Trypanothione Syntethase Inhibitors for the Treatment of Chagas Disease

JUAN I. ALICE; MARÍA L. SBARAGLINI; JUAN F. MORALES; CAROLINA L. BELLERA; CATALINA ALBA SOTO; ALAN TALEVI

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Protozoología, Sociedad Argentina de Hematología, Sociedad Argentina de Fisiología, Sociedad Argentina de Farmacología Experimental, Sociedad Argentina de Biología, Sociedad Argentina de Biofísica, Sociedad Argentina de Investigación

Chagas disease is an endemic parasitic disease that mainly affectsLatin America. The currently available medication display ahigh incidence of adverse effects and low efficacy in the chronicphase of infection in adults. Thus, it is very important to find newtherapies with higher clinical efficacy and safety profiles.Computer-aided drug repositioning may contribute to the systematicidentification of new pharmacological applications for existingdrugs, thus allowing the development of innovative therapeutic solutionsin a cost- and time-efficient manner.Here, we report the development and validation of ligand-based insilico models aimed at the identification of trypanothione sintethase(TryS) inhibitors. Such enzyme is essential for the biosynthesis oftrypanothione, a key metabolite for the maintenance of the redoxbalance and defense against oxidative stress in the parasite. Themodels were inferred and validated from the molecular structures of109 compounds previously assayed against TryS.We built 1000 individual classificatory models capable of differentiatingmolecules with and without inhibitory effect against TryS. Formodel validation, a pilot virtual screening in silico campaign was performedagainst a drug library containing a small proportion of knowninhibitors spread among decoys generated through the enhancedDirectory of Useful Decoys. Based on the results, we resort to ensemblelearning to obtain a 10-model combination which was laterapplied in the in silico screening of DrugBank 3.0 and Sweetlead.Twenty-one hits were classified as potential TryS inhibitors. 10 ofthem were acquired and assayed against T. cruzi trypomastigotes