Indexing
All Issues
Submission
Author Guidelines
Reviewers
Editorial Members
Publication Fee
Vol.5 , No. 1, Publication Date: Jan. 10, 2020, Page: 1-7
. 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.&picture=http://www.aascit.org/aascit/decorators/img/journal/809.jpg)
| [1] | Pedronel Araque Marín, Faculty of Medicine, University EIA, Envigado, Colombia. |
| [2] | 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.
Keywords
Trypanosoma Cruzi, Benznidazole, Resistance, Quantum Mechanics, Molecular Mechanics
Reference
| [01] | M. S. Lopes et al., “Synthesis and evaluation of the anti-parasitic activity of aromatic nitro compounds,” Eur. J. Med. Chem., vol. 46, no. 11, pp. 5443–5447, 2011. |
| [02] | C. T. Acero et al., “New Scenarios of Chagas Disease Transmission in Northern Colombia,” J. Parasitol. Res., vol. 2017, 2017. |
| [03] | M. A. Miles, A. A. De Souza, and M. Povoa, “Chagas Disease in the Amazon Basin 3. Ecotopes of 10 Triatomine Bug Species Hemiptera Heteroptera Reduviidae from the Vicinity of Belem-Para State Brazil,” J. Med. Entomol., vol. 18, no. 4, pp. 266–278, 1981. |
| [04] | O. Pung, C. Banks, D. Jones, and M. Krissinger, “Trypanosoma cruzi in Wild Raccoons, Opossums, and Triatomine Bugs in Southeast Georgia U.S.A.,” J. Parasitol., vol. 81, no. 2, pp. 324–326, 2018. |
| [05] | G. A. Schmunis and Z. E. Yadon, “Chagas disease: A Latin American health problem becoming a world health problem,” Acta Trop., vol. 115, no. 1–2, pp. 14–21, 2010. |
| [06] | World Organization Health, “Worldwide distribution of chagas disease” 2010. [Online]. Available: http://www.who.int/chagas/Global_distribution_Chagas_disease_2006_2010.pdf?ua=1. |
| [07] | World Organization Health, “Chagas disease (American Trypanosomiasis),” Fact sheet, 2017. [Online]. Available: http://www.who.int/mediacentre/factsheets/fs340/en/. |
| [08] | A. Rassi Jr, A. Rassi, and J. A. Marin-Neto, “Chagas disease,” Lancet, vol. 375, no. 9723, pp. 1388–1402, 2010. |
| [09] | C. J. Schofield, J. Jannin, and R. Salvatella, “The future of Chagas disease control,” Trends Parasitol., vol. 22, no. 12, pp. 583–588, 2006. |
| [10] | J. Gascon et al., “[Diagnosis, management and treatment of chronic Chagas’ heart disease in areas where Trypanosoma cruzi infection is not endemic],” Rev Esp Cardiol, vol. 60, no. 3, pp. 285–293, 2007. |
| [11] | S. Patterson and S. Wyllie, “Nitro drugs for the treatment of trypanosomatid diseases: Past, present, and future prospects,” Trends Parasitol., vol. 30, no. 6, pp. 289–298, 2014. |
| [12] | B. S. Hall, C. Bot, and S. R. Wilkinson, “Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites,” J. Biol. Chem., vol. 286, no. 15, pp. 13088–13095, 2011. |
| [13] | S. R. Wilkinson, M. C. Taylor, D. Horn, J. M. Kelly, and I. Cheeseman, “A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes,” Proc. Natl. Acad. Sci., vol. 105, no. 13, pp. 5022–5027, 2008. |
| [14] | M. Boiani et al., “Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: Is oxidative stress involved?,” Biochem. Pharmacol., vol. 79, no. 12, pp. 1736–1745, 2010. |
| [15] | C. écile Viodé et al., “Enzymatic reduction studies of nitroheterocycles,” Biochem. Pharmacol., vol. 57, no. 5, pp. 549–557, 1999. |
| [16] | S. F. Cui, L. P. Peng, H. Z. Zhang, S. Rasheed, K. Vijaya Kumar, and C. H. Zhou, “Novel hybrids of metronidazole and quinolones: Synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin,” Eur. J. Med. Chem., vol. 86, pp. 318–334, 2014. |
| [17] | C. A. Haynes, R. L. Koder, A. F. Miller, and D. W. Rodgers, “Structures of nitroreductase in three states. Effects of inhibitor binding and reduction,” J. Biol. Chem., vol. 277, no. 13, pp. 11513–11520, 2002. |
| [18] | A. M. Mejia, G. Fernández, and O. Triana-chávez, Trypanosoma cruzi strains resistant to benznidazole occurring in Colombia, vol. 32, no. 3. 2012. |
| [19] | A. M. Mejia et al., “Benznidazole-resistance in trypanosoma cruzi is a readily acquired trait that can arise independently in a single population,” J. Infect. Dis., vol. 206, no. 2, pp. 220–228, 2012. |
| [20] | L. Zhang and R. L. Tarleton, “Parasite persistence correlates with disease severity and localization in chronic Chagas’ disease.” J. Infect. Dis., vol. 180, no. 2, pp. 480–486, 1999. |
| [21] | S. R. Wilkinson and J. M. Kelly, “Trypanocidal drugs: mechanisms, resistance and new targets,” Expert Rev. Mol. Med., vol. 11, no. October 2009, p. e31, 2009. |
| [22] | M. C. O. Campos, L. L. Leon, M. C. Taylor, and J. M. Kelly, “Benznidazole-resistance in Trypanosoma cruzi: Evidence that distinct mechanisms can act in concert,” Mol. Biochem. Parasitol., vol. 193, no. 1, pp. 17–19, 2014. |
| [23] | A. Soto-Ospina and P. Araque Marín, “In Silico Prediction of the Structural Model of the Parasite Trypanosoma cruzi Nitroreductase Enzyme and Its Structural Validation,” J. Bioinform. Comput. Biol., vol. 2, no. 2, pp. 7–14, 2017. |
| [24] | J. Yang, R. Yan, A. Roy, D. Xu, P. J, and Y. Zhang, “The I-TASSER Suite: Protein structure and function prediction,” Nat Methods, vol. 12, no. 1, pp. 7–8, 2015. |
| [25] | A. Roy, A. Kucukural, and Y. Zhang, “I-TASSER: a unified platform for automated protein structure and function prediction,” Nat. Protoc., vol. 5, no. 4, pp. 725–738, 2010. |
| [26] | Y. Zhang, “I-TASSER server for protein 3D structure prediction.” BMC Bioinformatics, vol. 9, p. 40, 2008. |
| [27] | A. M. Waterhouse, J. B. Procter, D. M. A. Martin, M. Clamp, and G. J. Barton, “Jalview Version 2-A multiple sequence alignment editor and analysis workbench,” Bioinformatics, vol. 25, no. 9, pp. 1189–1191, 2009. |
| [28] | M. a Larkin et al., “Clustal W and Clustal X version 2.0.,” Bioinformatics, vol. 23, no. 21, pp. 2947–8, Nov. 2007. |
| [29] | E. F. Pettersen et al., “UCSF Chimera - A visualization system for exploratory research and analysis,” J. Comput. Chem., vol. 25, no. 13, pp. 1605–1612, 2004. |
| [30] | M. J Dewar, E. G. Zoebisch, E. F. Healy, and J. P. Stewart, “AM1: A Quantum Mechanical Molecular Model,” J. Am. Chem. Soc., vol. 49, no. June, pp. 3903–3909, 1993. |
| [31] | M. W. Van Der Kamp and A. J. Mulholland, “Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology,” Biochemistry, vol. 52, no. 16, pp. 2708–2728, 2013. |
| [32] | R. B. Murphy, D. M. Philipp, and R. a Friesner, “A mixed quantum mechanics/molecular mechanics (QM/MM) method for large-scale modeling of chemistry in protein environments,” J. Comput. Chem., vol. 21, no. 16, pp. 1442–1457, 2000. |
| [33] | Wavefunction, “Spartan 14’.” Wavefunction, 18401 Von Karman Avenue, Suite 370 Irvine, CA 92612 USA, 1991. |
| [34] | Y. Zou et al., Systematic study of imidazoles inhibiting IDO1 via the integration of molecular mechanics and quantum mechanics calculations, vol. 131. Elsevier Masson SAS, 2017. |
| [35] | J. R. Silva, A. E. Roitberg, and C. N. Alves, “A QM/MM free energy study of the oxidation mechanism of dihydroorotate dehydrogenase (class 1A) from lactococcus lactis,” J. Phys. Chem. B, vol. 119, no. 4, pp. 1468–1473, 2015. |
| [36] | C. Alves, J. Silva, and A. Roitberg, “Insights into the Mechanism of Oxidation of Dihydroorotate to Orotate Catalysed by Human Class 2 Dihydroorotate Dehydrogenase: A QM/MM Free Energy Study Cláudio,” Phys. Chem. Chem. Phys., vol. 4, pp. 1–8, 2015. |
| [37] | S. Yoneda, R. P. de S. Carvalho, and M. Quiroga, “Aspects of pyrimidine biosynthesis of Trypanosoma cruzi,” Rev. Med. Trop., vol. 16, pp. 324–327, 1974. |
| [38] | D. J. Hammond and W. Gutteridge, “Enzymes of pyrimidine biosynthesis in Trypanosoma cruzi.,” North-holl. Biomed. Press, vol. 118, no. 2, pp. 259–262, 1980. |
