Preprint Article Version 1 This version is not peer-reviewed

Structural Relationship of Flavin Mononucleotide (FMN) and Type I Nitroreductase (NTR) of Trypanosoma cruzi in Resistance Testing with Benznidazole and Nifurtimox

Version 1 : Received: 31 May 2018 / Approved: 1 June 2018 / Online: 1 June 2018 (10:22:17 CEST)

How to cite: Araque Marín, P.; Soto Ospina, A. Structural Relationship of Flavin Mononucleotide (FMN) and Type I Nitroreductase (NTR) of Trypanosoma cruzi in Resistance Testing with Benznidazole and Nifurtimox. Preprints 2018, 2018060012 (doi: 10.20944/preprints201806.0012.v1). Araque Marín, P.; Soto Ospina, A. Structural Relationship of Flavin Mononucleotide (FMN) and Type I Nitroreductase (NTR) of Trypanosoma cruzi in Resistance Testing with Benznidazole and Nifurtimox. Preprints 2018, 2018060012 (doi: 10.20944/preprints201806.0012.v1).

Abstract

The Chagas disease (CD) is an endemic infectious disease in a large part of Latin America. This disease is characterized by the fact of being caused by the parasite Trypanosoma cruzi. Some symptoms of this disease are cardiopathies and gastrointestinal problems. Therefore, the commonly used treatment consists of nitro drugs such as benznidazole and nifurtimox, which target the nitroreductase enzyme that docks to the coenzyme flavin mononucleotide (FMN) and an oxidation-reduction reaction is generated. From this reaction, the nitro chemical function of benznidazole and nifurtimox is reduced to amine. This amine in turn interacts with the parasite´s DNA. In vitro tests experimentally help in the study of the parasite resistance to the drug benznidazole. This fact could explain how nonsynonymous mutations in the nitroreductase (NTR) enzyme do not allow the anchorage of the FMN coenzyme and as a consequence the parasite susceptibility to benznidazole decreases as the drug cannot be reduced. The structural relations from the hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) allow to detect the small changes generated in the system, considering a charge distribution associated with the structure, angle changes, interaction distances, potential surface calculations between the wildtype enzyme and the mutation found.

Subject Areas

Trypanosoma cruzi; benznidazole; resistance; quantum mechanics; molecular mechanics

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