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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Structure-Based Virtual Screening of New Benzoic Acid Derivatives as Trypanosoma cruzi Trans-sialidase Inhibitors

Author(s): Lenci Karina Vázquez-Jiménez, Alma Delia Paz-González, Alfredo Juárez-Saldivar, María Laura Uhrig, Rosalía Agusti, Alicia Reyes-Arellano, Benjamín Nogueda-Torres and Gildardo Rivera*

Volume 17, Issue 7, 2021

Published on: 06 May, 2020

Page: [724 - 731] Pages: 8

DOI: 10.2174/1573406416666200506084611

Price: $65


Background: Chagas disease, caused by the parasite Trypanosoma cruzi, represents a worldwide epidemiological, economic, and social problem. In the last decades, the trans-sialidase enzyme of Trypanosoma cruzi has been considered an attractive target for the development of new agents with potential trypanocidal activity.

Objective: In this work, the aim was to find new potential non-sugar trans-sialidase inhibitors using benzoic acid as a scaffold.

Methods: A structure-based virtual screening of the ZINC15 database was carried out. Additionally, the enzyme and trypanocidal activity of the selected compounds was determined.

Results: The results of this work detected 487 compounds derived from benzoic acid as potential transsialidase inhibitors with a more promising binding energy value (< -7.7 kcal/mol) than the known inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA). In particular, two lead compounds, V1 and V2, turned out to be promising trans-sialidase inhibitors. Even though the trypanocidal activity displayed was low, these compounds showed trans-sialidase inhibition values of 87.6% and 29.6%, respectively.

Conclusion: Structure-based virtual screening using a molecular docking approach is a useful method for the identification of new trans-sialidase inhibitors.

Keywords: Virtual screening, molecular docking, trans-sialidase, Trypanosoma cruzi, trypanocidal activity, enzymatic inhibition.

Graphical Abstract
Schmunis, G.A. Epidemiology of Chagas disease in non-endemic countries: the role of international migration. Mem. Inst. Oswaldo Cruz, 2007, 102(1)(Suppl. 1), 75-85.
[] [PMID: 17891282]
Pereira, K.S.; Schmidt, F.L.; Barbosa, R.L.; Guaraldo, A.M.; Franco, R.M.; Dias, V.L.; Passos, L.A. Transmission of chagas disease (American trypanosomiasis) by food. Adv. Food Nutr. Res., 2010, 59, 63-85.
[] [PMID: 20610174]
Pérez-Molina, J.A.; Perez, A.M.; Norman, F.F.; Monge-Maillo, B.; López-Vélez, R. Old and new challenges in Chagas disease. Lancet Infect. Dis., 2015, 15(11), 1347-1356.
[] [PMID: 26231478]
Henrissat, B.; Bairoch, A. Updating the sequence-based classification of glycosyl hydrolases. Biochem. J., 1996, 316(Pt 2), 695-696.
[] [PMID: 8687420]
Arioka, S.; Sakagami, M.; Uematsu, R.; Yamaguchi, H.; Togame, H.; Takemoto, H.; Hinou, H.; Nishimura, S. Potent inhibitor scaffold against Trypanosoma cruzitrans-sialidase. Bioorg. Med. Chem., 2010, 18(4), 1633-1640.
[] [PMID: 20097567]
Magesh, S.; Savita, V.; Moriya, S.; Suzuki, T.; Miyagi, T.; Ishida, H.; Kiso, M. Human sialidase inhibitors: design, synthesis, and biological evaluation of 4-acetamido-5-acylamido-2-fluoro benzoic acids. Bioorg. Med. Chem., 2009, 17(13), 4595-4603.
[] [PMID: 19450982]
Neres, J.; Bonnet, P.; Edwards, P.N.; Kotian, P.L.; Buschiazzo, A.; Alzari, P.M.; Bryce, R.A.; Douglas, K.T. Benzoic acid and pyridine derivatives as inhibitors of Trypanosoma cruzitrans-sialidase. Bioorg. Med. Chem., 2007, 15(5), 2106-2119.
[] [PMID: 17218104]
Neres, J.; Brewer, M.L.; Ratier, L.; Botti, H.; Buschiazzo, A.; Edwards, P.N.; Mortenson, P.N.; Charlton, M.H.; Alzari, P.M.; Frasch, A.C.; Bryce, R.A.; Douglas, K.T. Discovery of novel inhibitors of Trypanosoma cruzitrans-sialidase from in silico screening. Bioorg. Med. Chem. Lett., 2009, 19(3), 589-596.
[] [PMID: 19144516]
Kashif, M.; Chacón-Vargas, K.F.; López-Cedillo, J.C.; Nogueda-Torres, B.; Paz-González, A.D.; Ramírez-Moreno, E.; Agusti, R.; Uhrig, M.L.; Reyes-Arellano, A.; Peralta-Cruz, J.; Ashfaq, M.; Rivera, G. Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzitrans-sialidase. Eur. J. Med. Chem., 2018, 156, 252-268.
[] [PMID: 30006170]
Sterling, T.; Irwin, J.J. ZINC 15--Ligand Discovery for Everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337.
[] [PMID: 26479676]
Buschiazzo, A.C.; Frasch, O. Campetella, Medium scale production and purification to homogeneity of a recombinant trans-sialidase from Trypanosoma cruzi. Cell. Mol. Biol., 1996, 42703.e710
Cano, M.E.; Agusti, R.; Cagnoni, A.J.; Tesoriero, M.F.; Kovensky, J.; Uhrig, M.L.; de Lederkremer, R.M. Synthesis of divalent ligands of β-thio- and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzitrans-sialidase. Beilstein J. Org. Chem., 2014, 10, 3073-3086.
[] [PMID: 25670976]
Brener, Z. Biology of Trypanosoma cruzi. Annu. Rev. Microbiol., 1973, 27, 347-382.
[] [PMID: 4201691]
Lara-Ramírez, E.E.; López-Cedillo, J.C.; Nogueda-Torres, B.; Kashif, M.; Garcia-Perez, C.; Bocanegra-Garcia, V.; Agusti, R.; Uhrig, M.L.; Rivera, G. An In vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method. Eur. J. Med. Chem., 2017, 132, 249-261.
[] [PMID: 28364659]
Muhammad, K.; Moreno-Herrera, A.; Villalobos-Rocha, J.C.; Nogueda-Torres, B.; Pérez-Villanueva, J. Karen Rodríguez-Villar, José Luis Medina-Franco, Peterson de Andrade, Ivone Carvalho and Gildardo Rivera. Benzoic Acid Derivatives with Trypanocidal Activity: Enzymatic Analysis and Molecular Docking Studies to Trans-sialidase. Molecules, 2017, 22(11), 1863.
Buschiazzo, A.; Amaya, M.F.; Cremona, M.L.; Frasch, A.C.; Alzari, P.M. The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis. Mol. Cell, 2002, 10(4), 757-768.
[] [PMID: 12419220]

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