Developing selective cruzain inhibitors through structure-based techniques

Abstract

Cruzain is the major Trypanosoma cruzi cysteine proteinase, a validated target for drug development against this parasite. T. cruzi is the etiological agent of Chagas Disease, a pathological condition from Latin America, considered a neglected disease. Benznidazole is the medicine currently used in the treatment of this disease in Brazil. Its efficacy is proven only in the acute phase of the disease, presenting many side effects which contribute to the treatment abandonment by the patients. Therefore, it is very important to develop alternative drugs, and this work aims to contribute in this sense. To do so, a virtual screening strategy employing molecular docking was proposed to search for possible cruzain inhibitors. A differential aspect of this work was the inclusion of the selectivity idea already in the screening step. This has been incorporated by docking molecules against cruzain, but also against the human homologous enzymes cathepsin L and B. Thereby, after the virtual screening protocol and visual inspection of top scoring compounds, eight hits that might be selective for cruzain were selected. Perspectives include the evaluation of these molecules in enzymatic assays and, if a hit is confirmed, design analogues with improved activity and selectivity.