Application of computer-aided drug repurposing in the search of new cruzipain inhibitors: discovery of amiodarone and bromocriptine inhibitory effects

BELLERA CL; BALCAZAR DE; ALBERCA L; LABRIOLA CA; CARRILLO C; TALEVI A

Rosario

Congreso; Congreso Iberoamericano de Bioinformática - Congreso Argentino de Bioinformática; 2013

Sociedad Iberoamericana de Bioinformática (SoIBio) & Asociación Argentina de Bioinformática y Biología Computacional (A2B2C)

Background Chagas disease (or American trypanosomiasis) is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi life-cycle includes both vertebrate (among them, man) and invertebrate (haematophagous triatomine bugs) hosts. Even though a series of control campaigns (with an emphasis on vector control) undertaken by World Health Organization, Pan American Health Organization and national authorities have dramatically reduced Chagas disease prevalence in the last fifteen years, there are still almost 10 million infected people and 25 million people at risk. Important advances made in the field of molecular biology of T. cruzi allow, however, the rational search of novel, specific antichagasic therapeutics. Cystein protease irreversible inhibitors are among the most investigated candidates against T. cruzi. Cruzipain (Cz), the major cystein protease of the parasite, has been particularly explored as new drug target. Materials and methods The aim of this work was to develop and implement a computational ligand-based model capable of identifying new reversible cruzipain inhibitors, to be applied in a virtual screening campaign to find new antichagasic drug candidates. We present the development of a 2D classification model derived from a 163-compound dataset which includes both Cz inhibitors and non-inhibitors. The model has been applied later in a virtual screening (VS) campaign to explore the DrugBank database, which compiles approved and investigational drugs, in order to identify novel Cz reversible inhibitors. Four candidates were acquired and tested on cruzipain activity and T. cruzi cultures in order to validate our model?s predictions. Results and Conclusions From 6684 small approved and investigational molecules of the DrugBank 3.0 database, 256 candidates belonging to the model?s applicability domain presented a model score above the selected threshold; 54 of them correspond to approved drugs, which are the straightforward candidates for repositioning purposes. Two out of four candidates experimentally tested in enzymatic and proliferation assays showed dose-dependent inhibition on cruzipain. Those included amiodarone (approved as antiarrhythmic) and bromocriptine (traditionally used against Parkinson and more recently repurposed for the treatment of diabetes). The candidates also showed clear effects on T. cruzi proliferation and morphology. The results illustrate the possibilities of computer-aided drug repositioning in the search of novel medications for neglected diseases.