Chagas disease. Study of the Benznidazole-aldo-keto reductase interaction from a computational perspective

TRUJILLO, PABLO; GARAVAGLIA, PATRICIA ANDREA; ADUVIRI, SEBASTIAN; ALVAREZ, G; ASCIUTTO E; CANNATA, JOAQUÍN J B; GABRIELA ANDREA GARCIA; PICKHOLZ, MONICA

Buenos Aires

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Protozoología; 2022

Sociedad Argentina de Protozoología

Chagas disease, caused by the protozoan Trypanosoma cruzi, is considered a neglected tropical disease and affects more than 6 million people in the Americas. The current treatment of T. cruzi infection is based on nitro-heterocyclic compounds. These drugs are effective in the acute phase but present low efficacy in the chronic phase of the infection. It is known that nitro-heterocyclic compounds need to be reduced by parasite reductases to exert their trypanocidal effects; however, the mechanism of action is not clearly understood. Recent research suggests that the T. cruzi aldo-keto reductase (TcAKR) has affinity for Benznidazole (Bz), the drug used for Chagas treatment, and is involved in the resistance to this drug1. Protein–ligand interactions are fundamental to almost all processes studied for live sciences; chemical interactions and biological recognition are steep fundamentally in discovering new drugs. Success depends on the interaction of the ligand with highly specific sites in the protein. In this work we explored the interaction of TcAKR with Bz, using computer techniques. The goal was to identify possible sites of high affinity for the drug within the protein. In order to boost the protein-ligand match, we performed Molecular Dynamics (MD) simulations with different Bz-TcAKR ratios. This sampling allowed us to identify regions in the protein with affinity for the drug. Using this tool we were able to study dynamical properties of the protein with and without the drug. Besides, main specific interaction between the drug and the protein were identified, like hydrogen bond and salt bridges. Calculations allowed us to identify possible site of binding by comparison their free energy (MMPGSA). These studies provide new insights about TcAKR-Bz interaction that could favor the development of new strategies to attack the parasite.