Discovery of a Potential Benzimidazole-Derived Cruzain Inhibitor for Chagas Disease: Virtual Screening, ADMET Analysis, Molecular Dynamics and Binding Energy Calculations

Neglected Tropical Diseases often receive insufficient attention and investment from the pharmaceutical industry despite their significant global health burden. Among these diseases, Chagas disease affects approximately 8 million people worldwide, with Trypanosoma cruzi ( T. cruzi) identified as its causative agent. Cruzain (Cz) enzyme plays a critical role in the life cycle of T. cruzi and serves as a validated molecular target for developing new therapeutic compounds. This study aimed to identify potential Cz inhibitors using a molecular database and advanced computational techniques. The compounds were first screened through molecular docking, and those demonstrating favorable energetic profiles and interactions with the catalytic triad of Cz were selected for further analysis. Among the top ten docking results, the identified compounds exhibited higher binding energy values than the co-crystallized ligand of the Cz enzyme. The chosen molecules were further evaluated using in silico methods to predict their toxicity profiles and pharmacokinetic properties. Molecular dynamics simulations were performed on the B95 and LMM3 compounds to enhance the analysis and evaluate their conformational stability, followed by binding free energy calculations. Our results suggest that these compounds, particularly LMM3, may be promising T. cruzi inhibitors targeting the Cz enzyme.