Generic placeholder image

Anti-Infective Agents


ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

Research Article

Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

Author(s): Vinícius Guimarães da Paixão and Samuel Silva da Rocha Pita*

Volume 18, Issue 4, 2020

Page: [398 - 418] Pages: 21

DOI: 10.2174/2211352518666200131121308


Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism.

Methods: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR.

Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities.

Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

Keywords: Leishmaniasis, Leishmania infantum, trypanothione reductase, natural products, biodiversity, virtual screening.

Graphical Abstract
Özbilgin, A.; Töz, S.; Harman, M.; Günaştı Topal, S.; Uzun, S.; Okudan, F.; Güngör, D.; Erat, A.; Ertabaklar, H.; Ertuğ, S.; Gündüz, C.; Çavuş, İ.; Karakuş, M.; Östan Ural, İ.; Ölgen, M.K.; Kayabaşı, Ç.; Kurt, Ö.; Özbel, Y. The current clinical and geographical situation of cutaneous leishmaniasis based on species identification in Turkey. Acta Trop., 2019, 190, 59-67.
[] [PMID: 30412694]
da Rocha, I.C.M.; Dos Santos, L.H.M.; Coura-Vital, W.; da Cunha, G.M.R.; Magalhães, F.D.C.; da Silva, T.A.M.; Morais, M.H.F.; Oliveira, E.; Reis, I.A.; Carneiro, M. Effectiveness of the Brazilian Visceral Leishmaniasis Surveillance and Control Programme in reducing the prevalence and incidence of Leishmania infantum infection. Parasit. Vectors, 2018, 11(1), 586.
[] [PMID: 30419944]
Chatelain, E.; Ioset, J.R. Drug discovery and development for neglected diseases: the DNDi model. Drug Des. Devel. Ther., 2011, 5, 175-181.
[PMID: 21552487]
Pinto, E.G.; Tempone, A.G. Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach. J. Venom. Anim. Toxins Incl. Trop. Dis., 2018, 24, 29.
[] [PMID: 30386379]
McCulley, S.F.; Setzer, W.N. An in silico investigation of anti-Chagas phytochemicals. Curr. Clin. Pharmacol., 2014, 9(3), 205-257.
[] [PMID: 23173969]
Rodríguez-Becerra, J.; Cáceres-Jensen, L.; Hernández-Ramos, J.; Barrientos, L. Identification of potential trypanothione reductase inhibitors among commercially available β-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking. Mol. Divers., 2017, 21(3), 697-711.
[] [PMID: 28656524]
Tiwari, N.; Tanwar, N.; Munde, M. Molecular insights into trypanothione reductase-inhibitor interaction: A structure-based review. Arch. Pharm. (Weinheim), 2018, 351(6)e1700373
[] [PMID: 29672908]
Turcano, L.; Torrente, E.; Missineo, A.; Andreini, M.; Gramiccia, M.; Di Muccio, T.; Genovese, I.; Fiorillo, A.; Harper, S.; Bresciani, A.; Colotti, G.; Ilari, A. Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening. PLoS Negl. Trop. Dis., 2018, 12(11)e0006969
[] [PMID: 30475811]
Ferreira, R.S.; Guido, R.V.; Andricopulo, A.D.; Oliva, G. In silico screening strategies for novel inhibitors of parasitic diseases. Expert Opin. Drug Discov., 2011, 6(5), 481-489.
[] [PMID: 22646074]
Montanari, C.A.; Bolzani, V.S. Planejamento racional de fármacos baseado em produtos naturais. Quim. Nova, 2001, 24.
Rodrigues, R.P.; Mantoani, S.P.; Almeida, J.R.d.; Pinsetta, F.R.; Semighini, E.P.; Silva, V.B.d.; Silva, C.H.T.P.d. Virtual Screening Strategies in Drug Design. Revista Virtual de Química, 2012, 4, 39.
Montanari, C.A. Química Medicinal: Métodos e Fundamentos em Planejamento de Fármacos; EDUSP: São Paulo, 2011.
Baiocco, P.; Franceschini, S.; Ilari, A.; Colotti, G. Trypanothione reductase from Leishmania infantum: cloning, expression, purification, crystallization and preliminary X-ray data analysis. Protein Pept. Lett., 2009, 16(2), 196-200.
[] [PMID: 19200044]
Baiocco, P.; Ilari, A.; Ceci, P.; Orsini, S.; Gramiccia, M.; Di Muccio, T.; Colotti, G. Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation. ACS Med. Chem. Lett., 2010, 2(3), 230-233.
[] [PMID: 24900299]
Baiocco, P.; Poce, G.; Alfonso, S.; Cocozza, M.; Porretta, G.C.; Colotti, G.; Biava, M.; Moraca, F.; Botta, M.; Yardley, V.; Fiorillo, A.; Lantella, A.; Malatesta, F.; Ilari, A. Inhibition of Leishmania infantum trypanothione reductase by azole-based compounds: a comparative analysis with its physiological substrate by X-ray crystallography. ChemMedChem, 2013, 8(7), 1175-1183.
[] [PMID: 23733388]
Colotti, G.; Baiocco, P.; Fiorillo, A.; Boffi, A.; Poser, E.; Chiaro, F.D.; Ilari, A. Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs. Future Med. Chem., 2013, 5(15), 1861-1875.
[] [PMID: 24144416]
Venkatesan, S.K.; Dubey, V.K. Footprinting of inhibitor interactions of in silico identified inhibitors of trypanothione reductase of Leishmania parasite. ScientificWorldJournal, 2012.2012963658
[] [PMID: 22550471]
Venkatesan, S.K.; Saudagar, P.; Shukla, A.K.; Dubey, V.K. Screening natural products database for identification of potential antileishmanial chemotherapeutic agents. Interdiscip. Sci., 2011, 3(3), 217-231.
[] [PMID: 21956744]
Venkatesan, S.K.; Shukla, A.K.; Dubey, V.K. Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum. J. Comput. Chem., 2010, 31(13), 2463-2475.
[PMID: 20340105]
Keramagi, A.R.; Skariyachan, S. Prediction of binding potential of natural leads against the prioritized drug targets of chikungunya and dengue viruses by computational screening. 3 Biotech , 2018, 8, 274..
Da Silva, B.J.M.; Hage, A.A.P.; Silva, E.O.; Rodrigues, A.P.D. Medicinal plants from the Brazilian Amazonian region and their antileishmanial activity: a review. J. Integr. Med., 2018, 16(4), 211-222.
[] [PMID: 29691188]
Da Silva, B.J.M.; Souza-Monteiro, J.R.; Rogez, H.; Crespo-López, M.E.; Do Nascimento, J.L.M.; Silva, E.O. Selective effects of Euterpe oleracea (açai) on Leishmania (Leishmania) amazonensis and Leishmania infantum. Biomed. Pharmacother., 2018, 97, 1613-1621.
[] [PMID: 29793323]
Imperatori, F.; Barlozzari, G.; Scardigli, A.; Romani, A.; Macri, G.; Polinori, N.; Bernini, R.; Santi, L. Leishmanicidal activity of green tea leaves and pomegranate peel extracts on L. infantum. Nat. Prod. Res., 2018, 1-7.
[PMID: 29863902]
Ortalli, M.; Ilari, A.; Colotti, G.; De Ionna, I.; Battista, T.; Bisi, A.; Gobbi, S.; Rampa, A.; Di Martino, R.M.C.; Gentilomi, G.A.; Varani, S.; Belluti, F. Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. Eur. J. Med. Chem., 2018, 152, 527-541.
[] [PMID: 29758517]
Kury, A.B.; Aleixo, A.; Bonaldo, A.B.; Marino, A.; Percequillo, A.; Prudente, A.L.C.; Azeredo-Espin, A.M.L.; Vieira, A.O.S.; Marques, C.A.; Peixoto, L.A.; Cruz, A.B.; Franco, B.D.G.M.; Inácio, C.A.; Bicudo, C.E.M.; Lamas, C.E.; Berg, C.V.D.; Magalhães, C.; Barros, C.F.; Umino, C.Y.; Costa, D.P.; Canhos, D.A.L.; Hajdu, E.; Kitajima, E.W.; Fantinatti-Garboggini, F.; Thompson, F.L.; Straube, F.C.; Peixoto, F.L.; Melo, G.A.; Lima, H.C.; Zaher, H.; Machado, I.; Santos, I.A.; Azevedo, J.L.; Grazia, J.; Dergam, J.A.; Pirani, J.R.; Sette, L.D.; Maia, L.C.; Melo, L.C.P.; Almeida, L.M.; Marinoni, L.; Anjos, L.; Simone, L.R.L.; Couri, M.S.; Barbosa, M.R.V.; Menezes, M.; Siqueira, M.F.; Lopes, M.A.; Stanton, M.; Hopkins, M.; Seleghim, M.H.R.; Simões, N.; Peixoto, O.L.; Toledo, P.M.; Fonseca, R.L.; Souza, R.D.F.; Giovanni, R.; Reis, R.E.; Torres, R.A.; Vazoller, R.F.; Souza, S.; Mello, S.C.M.; Oliveira, V.M.; Canhos, V.P.; Coradin, V.R.; Araújo, W.L.; Thomas, W.W.; Wosiack, W.B. Centro de Gestão e Estudos Estratégicos; , 2006, p. 324.
Barreiro, E.J.; Bolzani, v.s. biodiversity: potential source for drug discovery. Quim. Nova, 2009, 32, 9.
NatProDB Available from:.
Valli, M.; dos Santos, R.N.; Figueira, L.D.; Nakajima, C.H.; Castro-Gamboa, I.; Andricopulo, A.D.; Bolzani, V.S. Development of a natural products database from the biodiversity of Brazil. J. Nat. Prod., 2013, 76(3), 439-444.
[] [PMID: 23330984]
Pires, D.E.; Blundell, T.L.; Ascher, D.B. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem., 2015, 58(9), 4066-4072.
[] [PMID: 25860834]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[] [PMID: 19399780]
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity—A rapid access to atomic charges ,. 1980.
Molecular Graphic Laboratory TSRI. Available from:.
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1998, 19, 1639-1662.
Bouvier, G.; Evrard-Todeschi, N.; Girault, J.P.; Bertho, G. Automatic clustering of docking poses in virtual screening process using self-organizing map. Bioinformatics, 2010, 26(1), 53-60.
[] [PMID: 19910307]
Braga, R.C.; Alves, V.M.; Silva, M.F.; Muratov, E.; Fourches, D.; Tropsha, A.; Andrade, C.H. Tuning HERG out: antitarget QSAR models for drug development. Curr. Top. Med. Chem., 2014, 14(11), 1399-1415.
[] [PMID: 24805060]
Braga, R.C.; Alves, V.M.; Silva, M.F.; Muratov, E.; Fourches, D.; Lião, L.M.; Tropsha, A.; Andrade, C.H. Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity. Mol. Inform., 2015, 34(10), 698-701.
[] [PMID: 27490970]
Irwin, J.J.; Duan, D.; Torosyan, H.; Doak, A.K.; Ziebart, K.T.; Sterling, T.; Tumanian, G.; Shoichet, B.K. An Aggregation Advisor for Ligand Discovery. J. Med. Chem., 2015, 58(17), 7076-7087.
[] [PMID: 26295373]
Baell, J.B.; Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 53(7), 2719-2740.
[] [PMID: 20131845]
Lagorce, D.; Sperandio, O.; Galons, H.; Miteva, M.A.; Villoutreix, B.O. FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects. BMC Bioinformatics, 2008, 9, 396.
[] [PMID: 18816385]
Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model., 2015, 55(2), 460-473.
[] [PMID: 25558886]
von Korff, M.; Sander, T. Toxicity-indicating structural patterns. J. Chem. Inf. Model., 2006, 46(2), 536-544.
[] [PMID: 16562981]
Mantsyzov, A.B.; Bouvier, G.; Evrard-Todeschi, N.; Bertho, G. Contact-based ligand-clustering approach for the identification of active compounds in virtual screening. Adv. Appl. Bioinform. Chem., 2012, 5, 61-79.
[PMID: 23055752]
Chan, C.; Yin, H.; Garforth, J.; McKie, J.H.; Jaouhari, R.; Speers, P.; Douglas, K.T.; Rock, P.J.; Yardley, V.; Croft, S.L.; Fairlamb, A.H. Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs (vol 41, pg 150, 1998). J. Med. Chem., 1998, 41, 4910-4910.
Silva Da Rocha Pita, S.; Batista, P.R.; Albuquerque, M.G.; Pascutti, P.G. Molecular dynamics simulations of peptide inhibitors complexed with Trypanosoma cruzi trypanothione reductase. Chem. Biol. Drug Des., 2012, 80(4), 561-571.
[] [PMID: 22702225]
Bond, C.S.; Zhang, Y.; Berriman, M.; Cunningham, M.L.; Fairlamb, A.H.; Hunter, W.N. Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors. Structure, 1999, 7(1), 81-89.
[] [PMID: 10368274]
Bailey, S.; Smith, K.; Fairlamb, A.H.; Hunter, W.N. Substrate interactions between trypanothione reductase and N1-glutathionylspermidine disulphide at 0.28-nm resolution. Eur. J. Biochem., 1993, 213(1), 67-75.
[] [PMID: 8477734]
da Paixão, G.V.; S.R., Pita S.: Virtual Screening applied to search of inhibitors of Trypanosoma cruzi Trypanothione Reductase employing the Natural Products Database from Bahia state (NatProDB). Revista Virtual de Química, 2016, 8, 1289-1310.
Pita, S.S.R.P.P.G. Alvos Terapêuticos na Doença de Chagas: a Tripanotiona Redutase como Foco. Revista Virtual de Química, 2011, 3, 307-324.
Khan, M.O.; Austin, S.E.; Chan, C.; Yin, H.; Marks, D.; Vaghjiani, S.N.; Kendrick, H.; Yardley, V.; Croft, S.L.; Douglas, K.T. Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines. J. Med. Chem., 2000, 43(16), 3148-3156.
[] [PMID: 10956223]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[] [PMID: 11259830]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[] [PMID: 12036371]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43(21), 3867-3877.
[] [PMID: 11052792]
Tambunan, U.S.F.; Nasution, M.A.F.; Azhima, F.; Parikesit, A.A.; Toepak, E.P.; Idrus, S.; Kerami, D. Modification of S-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation. Drug Target Insights, 2017, 111177392817701726
[] [PMID: 28469408]
Who: Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. World Health Organization, 2010..

© 2022 Bentham Science Publishers | Privacy Policy