There are only two drugs for the treatment of Chagas disease, namely, nifurtimox and benznidazole, that can cause several adverse effects. Despite the effectiveness of these drugs in the disease's acute phase, they are not recognized as curative in the chronic phase, establishing the need for more effective treatment in all stages of the disease. Cruzain is an enzyme that plays a vital role in the life cycle of the etiologic agent, the protozoan Trypanosoma cruzi, being relevant as a therapeutic target in the planning of new drugs. Using molecular docking and dynamics simulations, we have investigated the structural and dynamic factors that can be involved in the enzyme inhibition process at the atomic-molecular level by benzimidazole compounds that are potent cruzain inhibitors with in vitro trypanocidal activity. The study suggests that these inhibitors bind cruzain through steric and hydrogen bonding interactions without altering its secondary structure content and protein compaction. Besides, we observed that these inhibitors decrease the correlation of movements between Cα-atoms of cruzain, increasing the number of atomic communities, mainly in the α-helix that presents the catalytic Cys25 residue. As expected, we also observed a correlation between the inhibitory activity of each inhibitor and their respective binding-free energies, reinforcing that the affinity of the complexes seems to be a relevant factor for enzymatic inhibition. Hence, the results presented in this work contribute to a better understanding of the cruzain enzyme inhibition mechanism through competitive and non-covalent inhibitors.Communicated by Ramaswamy H. Sarma.
Keywords: Cruzain; Molecular docking; Molecular dynamics; Molecular modeling; Trypanosoma cruzi.