Discovery of Trypanosoma cruzi Carbonic Anhydrase Inhibitors by a Combination of Ligand- and Structure-Based Virtual Screening.

Trypanosoma cruzi carbonic anhydrase (TcCA) has emerged as a promising therapeutic target for the treatment of Chagas disease. In this study, a sequential virtual screening strategy was employed to identify potential TcCA inhibitors. The workflow consisted of ligand-based virtual screening applied to diverse chemical libraries, followed by target-based molecular docking to refine the selection of compounds. Six candidates were selected for their in vitro evaluation against both the enzyme and the parasite. All of them confirmed inhibitory activity against TcCA, with three exhibiting Kis in the nanomolar or submicromolar range. Among these, Nitrofurantoin demonstrated significant inhibitory activity, with a Ki of 93 nM against TcCA and EC50 of 14.82 μM against T. cruzi trypomastigotes. These findings suggest that Nitrofurantoin is a promising lead compound for further optimization and highlight the therapeutic potential of TcCA as a drug target in Chagas disease.