International Journal of Bioinformatics and Computational Biology  
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Redox mechanism of Trypanosoma cruzi Resistance to Nitro Prodrugs Benznidazole and Nifurtimox
International Journal of Bioinformatics and Computational Biology
Vol.5 , No. 1, Publication Date: Jan. 10, 2020, Page: 1-7
2418 Views Since January 10, 2020, 572 Downloads Since Jan. 10, 2020

Pedronel Araque Marín, Faculty of Medicine, University EIA, Envigado, Colombia.


Alejandro Soto-Ospina, Faculty of Medicine, University of Antioquia, Molecular Genetic (GenMol), Medellin, Colombia.


Chagas disease is an endemic infectious disease caused by parasite Trypanosoma cruzi (T. cruzi). Common symptoms include heart and gastrointestinal disorders. Conventional treatment consists in the administration of antiparasitics nitro prodrugs (e.g. benznidazole and nifurtimox), which are activated by the Nitroreductase (NTR) enzyme - Flavin Mononucleotide (FMN) complex in the parasite. To understand the parasite's mechanisms of resistance to the drugs, we studied a mutant enzyme (Pro46Leu) and used software UCSF Chimera to render a tridimensional image of it. Then, we computed its molecular electronic structure and the complex were optimized based on the data of global minimum geometry and energy using the Spartan 14’ software for wave function, via semi-empirical method with the force field Austin Model 1 (AM1). The hybrid QM/MM structural relationships generated by the software allowed us to detect small changes to the system (distribution of charges, dipole interaction distances, potential energy surface, electrostatic potential map and shifting of angles in the wild-type and mutant enzymes). In addition, the integration between bioinformatics for the alignment and search of tertiary structures of a protein and quantum mechanics to analyse point changes of amino acids and protein folding are useful in explaining how the parasite develops a mechanism to resist the drugs and as a fast and accurate alternative to generate more effective antibiotics derivatives. Finally, using experimental analysis, we generated models to understand the mechanisms of adsorption of nitro prodrugs and the resistance of the parasite to these.


Trypanosoma Cruzi, Benznidazole, Resistance, Quantum Mechanics, Molecular Mechanics


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