In Silico Investigation of TATA-Binding Protein as a Therapeutic Target for Chagas Disease: Insights into FDA Drug Repositioning.

Background: Parasitic diseases, particularly Chagas disease caused by Trypanosoma cruzi, primarily affect developing countries but are now spreading to wealthier nations due to changing migration patterns. With approximately 8 to 9 million cases annually and a rise in drug resistance and side effects, there is an urgent need for new therapeutic approaches. Objectives: This study aimed to identify potential pharmacological compounds to target the TATA Binding Protein (TBP) of T. cruzi. Methods: Over eleven thousand FDA-approved pharmacological compounds were analyzed using in silico methods, including homology modeling, molecular docking, and molecular dynamics simulations. In addition, in vitro assays were conducted to assess the trypanocidal activity of promising candidates against T. cruzi epimastigotes and their selectivity toward macrophage J774.2. Results: Two compounds, DB00890 and DB07635, emerged as promising candidates, demonstrating significant potential against T. cruzi TBP. Compound DB00890 had trypanocidal activity against T. cruzi epimastigotes, with IC₅₀ values of 70.4 µM (SI 2.84) and 37.3 µM (SI 5.36) for the NINOA and A1 strains, respectively. Conclusions: Our findings suggest DB00890 is a promising candidate for the development of new agents against Chagas disease, with the potential for targeted therapies that minimize side effects. These results provide a strong foundation for further research into novel treatments for parasitic diseases caused by T. cruzi.