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Computational discovery of sulfonamide derivatives as potential inhibitors of the cruzain enzyme from T. cruzi by molecular docking, molecular dynamics and MM/GBSA approaches

ABSTRACT Chagas disease is caused by Trypanosoma cruzi (T. cruzi) protozoan and is considered by WHO as a neglected tropical disease, affecting almost 21 countries in the Americas. Until now, only two drugs are clinically recommended for its treatment, although these have limited efficacy and cause serious adverse reactions in the patients. Particularly, the Cruzain (Cz), a cysteine protease enzyme, has been established as a therapeutic target of T. cruzi. Here, the Cz binding mode of sulfonamide derivatives was investigated using fragment-based growing, molecular docking, molecular dynamics (MD) simulations and binding free energy approaches. Here, two new potent Cz inhibitors (named CP1 and CP4) were proposed from the previously evaluated dichlorothiophene-2-sulfonamide compound (named CP6). MD simulations show that CP1 and CP4 compounds were more stable than CP6. Besides, MM/GBSA approach suggests that new proposed compounds CP1 and CP4 (–26.10 and –23.81 kcal/mol, respectively) bind to Cz active site with lower binding free energy values than CP6 (–21.79 kcal/mol). These results suggested these two compounds could be candidate inhibitors against the Cz enzyme. Hence findings in our study can provide valuable information on the discovery of potent trypanocidal agents.