Arginine kinase catalyzes the reversible transphosphorylation between ADP and phosphoarginine which plays a critical role in the maintenance of cellular energy homeostasis. Arginine kinase from the protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, meets the requirements to be considered as a potential therapeutic target for rational drug design including being absent in its mammalian hosts. In this study a group of polyphenolic compounds was evaluated as potential inhibitors of arginine kinase using molecular docking techniques. Among the analyzed compounds with the lowest free binding energy to the arginine kinase active site (<-6.96kcal/mol), resveratrol was chosen for subsequent assays. Resveratrol inhibits 50% of recombinant arginine kinase activity at 325μM. The trypanocidal effect of resveratrol was evaluated on the T. cruzi trypomastigotes bursting from infected CHO K1 cells, with IC50=77μM. Additionally epimastigotes overexpressing arginine kinase were 5 times more resistant to resveratrol compared to controls. Taking into account that: (1) resveratrol is considered as completely nontoxic; (2) is easily accessible due to its low market price; and (3) has as a well-defined target enzyme which is absent in the mammalian host, it is a promising compound as a trypanocidal drug for Chagas disease.
Keywords: Arginine kinase; Chagas disease; Molecular docking; Polyphenols; Resveratrol; Trypanosoma cruzi.
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