Nereis. Interdisciplinary Ibero-American Journal of Methods, Modelling and Simulation.

Buscador

Application of molecular topology in the prediction of new compounds with anti-trypanosomal cytotoxic activity

Abstract

Chagas disease is a protozoan anthropozoonosis primarily transmitted by vectors. America is the main affected continent, although it is considered a worldwide neglected tropical disease. Only two drugs with a high toxicity level are available for its treatment. Because of this, it is necessary to make an effort in order to develop new effective and safe therapies. In this study, molecular topology was used to create a QSAR model to predict anti-trypanosomal cytotoxic activity in a group of 39 compounds. Linear discriminant analysis correctly classified 93.3 % of the active studied compounds. To predict the anti-trypanosomal potency, multilinear regression analysis was used; being this capable of explaining 90.8 % of the variance. Both analyses were validated by an internal “leave some out” test. The resulting model was applied to new compounds, selecting eight of them as potential active molecules that could be used in future preclinical studies.

References

World Health Organization. Integrating neglected tropical diseases into global health and development: fourth WHO report on neglected tropical diseases. World Health Organization; 2017.

Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018;391(10115):82-94.

Moretti NS, Mortara RA, Schenkman S. Trypanosoma cruzi. Trends Parasitol. 2020;36(4):404-5.

Messenger LA, Bern C. Congenital Chagas disease: current diagnostics, limitations and future perspectives. Curr Opin Infect Dis. 2018;31(5):415-21.

Cura CI, Lattes R, Nagel C, Gimenez MJ, Blanes M, Calabuig E, et al. Early Molecular Diagnosis of Acute Chagas Disease After Transplantation With Organs From Trypanosoma cruzi–Infected Donors. Am J Transplant. 2013;13(12):3253-61.

Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144(10):724-34.

Lana M de, Lopes LA, Martins HR, Bahia MT, Machado-de-Assis GF, Wendling AP, et al. Clinical and laboratory status of patients with chronic Chagas disease living in a vector-controlled area in Minas Gerais, Brazil, before and nine years after aetiological treatment. Mem Inst Oswaldo Cruz. 2009;104(8):1139-47.

Andrade ALSS, Martelli CMT, Oliveira RM, Silva SA, Aires AIS, Soussumi LMT, et al. benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. Am J Trop Med Hyg. 2004;71(5):594-7.

Estani SS, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am J Trop Med Hyg. 1998;59(4):526-9.

Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi Jr A, Rosas F, et al. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med. 2015;373(14):1295- 306.

Yun O, Lima MA, Ellman T, Chambi W, Castillo S, Flevaud L, et al. Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières. PLoS Negl Trop Dis. 2009;3(7):e488.

Melo-Filho CC, Braga RC, Muratov EN, Franco CH, Moraes CB, Freitas-Junior LH, et al. Discovery of new potent hits against intracellular Trypanosoma cruzi by QSAR-based virtual screening. Eur J Med Chem. 2019;163:649-59.

Paucar R, Moreno-Viguri E, Pérez-Silanes S. Challenges in Chagas disease drug discovery: a review. Curr Med Chem. 2016;23(28):3154-70.

Urbina JA. Ergosterol biosynthesis and drug development for Chagas disease. Mem Inst Oswaldo Cruz. 2009;104:311-8.

Maguire JH. Treatment of Chagas’ Disease —time is running out. Mass Medical Soc; 2015.

García-Doménech R, Gálvez J, de Julián-Ortiz J V, Pogliani L. Some new trends in chemical graph theory. Chem Rev. 2008;108(3):1127-69.

Amigó JM, Villar Amigó V, Falcó Montesinos A, Gálvez J. Topología molecular. Boletín la Soc Española Matemática Apl N. 2007;39.

Zanni R, Gálvez-Llompart M, García-Doménech R, Gálvez J. Latest advances in molecular topology applications for drug discovery. Expert Opin Drug Discov. 2015;10(9):945-57.

Martínez Rodríguez MÁ, Seguí López-Peñalver RJ, Alcácer Tomás G, Gálvez Álvarez J, García- Doménech R. Aplicación de la topología molecular a la predicción y optimización de la actividad repelente de mosquitos de derivados de la N-acylpiperidina. Nereis. 2014;(6):19-26.

Carrillo JS, Rizza C, Álvarez BE, Hernández D, JG, García-Doménech R. Aplicación de la topología molecular en la búsqueda de nuevos compuestos basados en Azaauronas derivados de las auronas naturales como potenciales antimaláricos. Application of Molecular Topology in the search for new composites based on Azaaurones derived. Nereis Interdiscip Ibero-American J Methods, Model Simul. 2017;9:49-62.

Mateo AJ, García RS, Sarmiento AM, Guidet LG, Gálvez J, García-Doménech R. Application of molecular topology for predicting the leishmanicidal activity of a group of compounds derived from pyrrolo [1,2-?] quinoxaline. An la Real Acad Nac Farm. 2016;82(3):317-23.

Rodríguez Grande C, Villalba de Gregorio B, Bort Carbonell M, Giordanelly Mendicoa C, Gálvez Álvarez J, García Doménech R. Aplicación de topología molecular a la predicción de la actividad frente a Trypanosoma cruzi de compuestos derivados nitrotriazoles. Nereis Rev Iberoam Interdiscip métodos, Model y simulación. 2016;(8):11-22.

Souard F, Okombi S, Beney C, Chevalley S, Valentin A, Boumendjel A. 1-Azaaurones derived from the naturally occurring aurones as potential antimalarial drugs. Bioorg Med Chem. 2010;18(15):5724-31.

Dragon for windows (software for molecular descriptor calculations), version 5.4., Talete srl.; Milan, Italy, 2006.

Kier LB, Hall LH. Molecular connectivity in structure-activity analysis. Research studies; 1986.

Gálvez J, García R, Salabert MT, Soler R. Charge indexes. New topological descriptors. J Chem Inf Comput Sci. 1994;34(3):520-5.

Wiener H. Structural determination of paraffin boiling points. J Am Chem Soc. 1947;69(1):17-20.

García-Doménech R, López-Peña W, Sanchez-Perdomo Y, Sanders JR, Sierra-Araujo MM, Zapata C, et al. Application of molecular topology to the prediction of the antimalarial activity of a group of uracil-based acyclic and deoxyuridine compounds. Int J Pharm. 2008;363(1-2):78-84.

Gálvez J, Gálvez-Llompart M, García-Domenech R. Introduction to molecular topology: basic concepts and application to drug design. Curr Comput Aided Drug Des. 2012;8(3):196-223.

Gramatica P, Sangion A. A historical excursus on the statistical validation parameters for QSAR models: a clarification concerning metrics and terminology. J Chem Inf Model. 2016;56(6):1127- 31.

Gálvez J, García-Doménech R, de Gregorio Alapont C, de Julián-Ortiz J V, Popa L. Pharmacological distribution diagrams: a tool for de novo drug design. J Mol Graph. 1996;14(5):272-6.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49(D1):D1388-95.

Marin-Neto JA, Rassi Jr A, Morillo CA, Avezum A, Connolly SJ, Sosa-Estani S, et al. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas’ cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am Heart J. 2008;156(1):37-43.

Morillo CA, Waskin H, Sosa-Estani S, del Carmen Bangher M, Cuneo C, Milesi R, et al. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: the STOPCHAGAS trial. J Am Coll Cardiol. 2017;69(8):939-47.

Downloads

Download data is not yet available.