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.