Find in Library

Chagas disease, caused by <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (<i>Hs</i>DHFR) inhibitors such as trimetrexate also inhibit <i>T. cruzi</i> DHFR-TS (<i>Tc</i>DHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new <i>Tc</i>DHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against <i>T. cruzi</i> infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to <i>Tc</i>DHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative <i>Tc</i>DHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on <i>T. cruzi</i> epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.