Abstract
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), 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 (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-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 T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-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 T. cruzi 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.
Highlights
American trypanosomiasis, known as Chagas disease, is a protozoan infectious disease caused by the parasite Trypanosoma cruzi (T. cruzi)
We propose the repositioning of food and drug administration (FDA)-approved drugs for the inhibition of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) of T. cruzi
It can be seen that the orientation of trimetrexate in this complex suggests that only one side of the structure influences the inhibition mechanism of TcDHFR-TS
Summary
Known as Chagas disease, is a protozoan infectious disease caused by the parasite Trypanosoma cruzi (T. cruzi). It affects approximately eight million people, mainly in Latin America. T. cruzi is transmitted in the feces of a triatomine vector, during blood meal intake. Other mechanisms of transmission include blood transfusion, organ transplantation and congenital transmission [1]. Chagas disease is usually asymptomatic in the acute phase; some common symptoms such as fever and portal-of-entry effects can occur. Cardiac disease affects around 30−40% of patients who suffer arrhythmias, tachycardia, heart failure and sudden death [2]
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