Computer-aided search of new antitrypanosomal polyamine analogs

ALBERCA L; BALCAZAR DE; FRACCAROLI L; CARRILLO C; TALEVI A

Mar del Plata

Congreso; X Congreso Argentino de Protozoología y Enfermedades Parasitarias; 2014

Sociedad Argentina de Protozoologìa

Chagas is a Latin-American endemic disease caused by Trypanosoma cruzi. Although its sanitary importance, there are still only two approved drugs for Chagas therapy: nifurtimox and benznidazole. Both present serious adverse effects and limited efficacy. Thus, there is a real sanitary need of new therapeutic alternatives. Recently, the role of computer-aided drug repositioning (i.e. searching for novel indications of already known, discontinued and/or shelved drugs) has been underlined as an efficient strategy to discover innovative medications for Chagas disease and other disorders traditionally labeled as neglected diseases. Here, we have applied computer-aided drug repositioning to search for new antichagasic polyamine analogs. Polyamines are typically found in high levels in fast proliferating cells such as cancerous cells and parasites. They mediate a number of essential functions for growth, proliferation and differentiation. Interestingly, T. cruzi lacks the enzyme responsible of the first step of the polyamines biosynthesis, thus being dependent on the uptake of polyamines. A database containing polyamine analogs with and without inhibitory effect on T. cruzi proliferation was compiled from literature. Afterwards, 100 computational models capable of discriminating between active and inactive polyamine analogs were inferred through application of Linear Discriminant Analysis as implemented in Statistica 10 software. After validating the models, the ten best models were combined through ensemble learning and applied in the virtual screening of the chemical repositories DrugBank 3.0 and Sweetlead, which compile approved and experimental drugs from the FDA and from other regulatory agencies worldwide, respectively. 31 new drug candidates were selected. On the basis of their structures, original therapeutic uses and safety, doses, costs and accessibility, a selection of these candidates will be tested on in vitro and in vivo cellular assays.