Computer-aided search of novel riboflavin analogs with antichagasic effects

SBARAGLINI ML; FRACCAROLI L; BALCAZAR DE; CARRILLO C; TALEVI A

Mar del Plata

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

Sociedad Argentina de Protozoologìa

Chagas disease is a parasitic disease endemic in Latin America, caused by the hemoflagelate Trypanosoma cruzi. Recent data from the World Health Organization indicate that there are around 10 million infected people and 25 million exposed to contagion. We have previously reported that the riboflavine permease from T. cruzi might be a promising new drug target. In this work we have applied a combination (ensemble) of molecular similarity search techniques to search for riboflavin analogs throughout chemical repositories DrugBank 3.0 and Sweetlead. Chemaxon (JChem 6.1.0 2013 www.chemaxon.com) and PowerMV (National Institute of Statistical Science V0.61) were used to compute a diversity of fingerprints (e.g. extended connectivity fingerprints, pharmacophere fingerprints, functional class fingerprints) and similarity metrics. These metrics were thus combined to enhance their enrichment ability. 80 compounds were selected as promising candidates; 2 of them (aloin and inosine) were acquired and their antiproliferative effect was tested on T. cruzi epimastigotes, counting, daily, the number of parasites per unit of volume in Neubauer chamber. Complementarily, MTT assay was used to assess the parasite viability. The present work constitutes and example of rational drug repurposing, in which novel therapeutic indications of already known drugs are sought with the aid of cheminformatic and bioinformatic tools.