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Cucurbit[7]uril as a possible nanocarrier for the antichagasic benznidazole: a computational approach

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Abstract

Benznidazole (BNZ) is one of the most recommended drugs for the acute phase of Chagas disease. However, its use has some limitations like low aqueous solubility, low biodisponibility, and considerable toxicity. To overcome these shortcomings, the use of nanocarrier agents is an interesting strategy that has been largely used in drug delivery. Therefore, herein molecular dynamics (MD) simulations and potential of mean force (PMF) technique were used to study the encapsulation of the BNZ into β-cyclodextrin (β-CD) and curcubit[7]uril (CB[7]) cavities in aqueous solution. Along the 50 ns of MD trajectory, the BNZ kept complexed with CB[7] and β-CD without significantly altering their structures and their second solvation shell. In the encapsulation process, the BNZ excluded 6 and 7 water molecules from the interior of CB[7] and β-CD, respectively. Both hosts were able to encapsulate the hydrophobic and hydrophilic groups of the BNZ guest. However, the PMF calculations showed that the BNZ@CB[7] complex is almost three times more stable than the BNZ@β-CD complex, with binding energies respectively equal to − 60.8 and − 21.8 kJ mol−1. Therefore, we highlight the CB[7] as a new macrocyclic host for drug delivery of BNZ that may be more efficient than the β-CD.

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References

  1. Chatelain, E.: Chagas disease drug discovery: toward a new era. J. Biomol. Screen. 20, 22–35 (2015)

    PubMed  Google Scholar 

  2. Docampo, R.: Recent developments in the chemotherapy of Chagas disease. Curr. Pharm. Des. 7, 1157–1164 (2001)

    CAS  PubMed  Google Scholar 

  3. Maya, J.D., Cassels, B.K., Iturriaga-Vasquez, P., Ferreira, J., Faúndez, M., Galanti, N., Ferreira, A., Morello, A.: Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp. Biochem. Physiol. Part A 146(146), 601–620 (2007)

    Google Scholar 

  4. Pinheiro, E., Brum-Soares, L., Reis, R., Cubides, J.-C.: Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev. Soc. Bras. Med. Trop. 50, 296–300 (2017)

    PubMed  Google Scholar 

  5. Caldas, I.S., Talvani, A., Caldas, S., Carneiro, C.M., da de LanaMatta Guedes, M.P.M., Bahia, M.T.: Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitol. Res. 103, 413–421 (2008)

    PubMed  Google Scholar 

  6. Mazzeti, A.L., Oliveira, L.T., Gonçalves, K.R., Schaun, G.C., Mosqueteira, V.C.F., Bahia, M.T.: Benznidazole self-emulsifying delivery system: A novel alternative dosage form for Chagas disease treatment. Eur. J. Pharm. Sci. 145, 105234 (2020)

    CAS  PubMed  Google Scholar 

  7. Silva, A.M.S., Caland, L.B., Doro, P.N.M., Oliveira, A.L.C.S.L., Aráujo-Júnior, R.F., Fernandes-Pedrosa, M.F., Egito, E.S.T., Silva-Junior, A.A.: Hydrophilic and hydrophobic polymeric benznidazole-loaded nanoparticles: physicochemical properties and in vitro antitumor efficacy. J. Drug Deliv. Sci. Technol. 51, 700–707 (2019)

    Google Scholar 

  8. Seremeta, K.P., Arrúa, E.V., Okulik, N.B., Salomon, C.J.: Development and characterization of benznidazole nano- and microparticles: a new tool for pediatric treatment of Chagas disease? Colloids Surf. B Biointerfaces 177, 169–177 (2019)

    CAS  PubMed  Google Scholar 

  9. Nhavene, E.P.F., da SilvaJunior, W.M.R.R.T., Gastelois, P.L., Venâncio, T., Nascimento, R., Batista, R.J.C., Machado, C.R., Macedo, W.A.A., de Sousa, E.M.B.: Chitosan grafted into mesoporous silica nanoparticles as benznidazol carrier for Chagas diseases treatment. Microporous Mesoporous Mater. 272, 265–275 (2018)

    CAS  Google Scholar 

  10. Morilla, M.J., Benavidez, P., Lopez, M.O., Bakas, L., Romero, E.L.: Development and in vitro characterisation of a benznidazole liposomal formulation. Int. J. Pharm. 249, 89–99 (2002)

    CAS  PubMed  Google Scholar 

  11. Vinuesa, T., Herráez, R., Oliver, L., Elizondo, E., Acarregui, A., Esquisabel, A., Pedraz, J.L., Ventosa, N., Veciana, J., Viñas, M.: Benznidazole nanoformulates: a chance to improve therapeutics for Chagas disease. Am. J. Trop. Med. Hyg. 97, 1469–1476 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Oliveira, E.C.V., Carneiro, Z.A., de Albuquerque, S., Marchetti, J.M.: Development and evaluation of a nanoemulsion containing ursolic acid: a promising trypanocidal agent. AAPS PharmSciTech. 18, 2551–2560 (2017)

    Google Scholar 

  13. Vermelho, A.B., Cardoso, V.D., Ricci, E., Dos Santos, E.P., Supuran, C.T.: Nanoemulsions of sulfonamide carbonic anhydrase inhibitors strongly inhibit the growth of Trypanosoma cruzi. J. Enzyme Inhib. Med. Chem. 33, 139–146 (2017)

    PubMed Central  Google Scholar 

  14. Streck, L., Sarmento, V.H., de Menezes, R.P., Fernandes-Pedrosa, M.F., Martins, A.M., da Silva-Júnior, A.A.: Tailoring microstructural, drug release properties, and antichagasic efficacy of biocompatible oil-in-water benznidazol-loaded nanoemulsions. Int. J. Pharm. 555, 36–48 (2019)

    CAS  PubMed  Google Scholar 

  15. Arrúa, E.C., Seremeta, K.P., Bedogni, G.R., Okulik, N.B., Salomon, C.J.: Nanocarriers for effective delivery of benznidazole and nifurtimox in the treatment of Chagas disease: areview. Acta Trop. 198, 105080 (2019)

    PubMed  Google Scholar 

  16. Quezada, C.Q., Azevedo, C.S., Charneau, S., Santana, J.M., Chorilli, M., Carneiro, M.B., Bastos, I.M.D.: Advances in nanocarriers as drug delivery systems in Chagas disease. Int. J. Nanomed. 14, 6407–6424 (2019)

    CAS  Google Scholar 

  17. Vikas, Y., Sandeep, K., Braham, D., Manjusha, C., Budhwar, V.: Cyclodextrin complexes: an approach to improve the physicochemical properties of drugs and applications of cyclodextrin complexes. Asian J. Pharm. 12, S3984 (2018)

    Google Scholar 

  18. Carneiro, S.B., Duarte, F.I.C., Heimfarth, L., Quintans, J.S.S., Quintans-Júnior, L.J., Júnior, V.L.V., Lima, A.A.N.: Cyclodextrin–drug inclusion complexes: in vivo and in vitro approaches. Int. J. Mol. Sci. 20, 64 (2019)

    Google Scholar 

  19. Español, E.S., Villamil, M.M.: Calixarenes: generalities and their role in improving the solubility, biocompatibility, stability, bioavailability, detection, and transport of biomolecules. Biomolecules 9, 90 (2019)

    PubMed Central  Google Scholar 

  20. Assaf, K.I., Nau, W.M.: Cucurbiturils: from synthesis to high-affinity, binding and catalysis. Chem. Soc. Rev. 44, 394 (2015)

    CAS  PubMed  Google Scholar 

  21. Yang, K., Pei, Y., Wen, J., Pei, Z.: Recent advances in pillar[n]arenes: synthesis and application based on host-guest interactions. Chem. Commun. 52, 9316–9326 (2016)

    CAS  Google Scholar 

  22. Sobrinho, J.L.S., Soares, M.F.L.R.: Improving the solubility of the antichagasic drug benznidazole through formation of inclusion complexes with cyclodextrins. Quim. Nova 34, 1534–1538 (2011)

    Google Scholar 

  23. Lyra, M.A.M., Soares-Sobrinho, J.L., Figueiredo, R.C.B.Q., Sandes, J.M., Lima, A.A.N., Tenório, R.P., Fontes, D.A.F., Santos, F.L.A., Rolim, L.A., Rolim-Neto, P.J.: Study of benznidazole–cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity. J. Incl. Phenom. Macrocycl. Chem. 73, 397–404 (2012)

    CAS  Google Scholar 

  24. Melo, P.N., Barbosa, E.G., Caland, L.B., Carpegianni, H., Garnero, C., Longhi, M., Fernades-Pedrosa, M.F., Silva-Júnior, A.A.: Host–guest interactions between benznidazole and beta-cyclodextrin in multicomponent complex systems involving hydrophilic polymers and triethanolamine in aqueous solution. J. Mol. Liq. 186, 147–156 (2013)

    Google Scholar 

  25. Bruschi, M.L.: Strategies to modify the drug release from pharmaceutical systems: 6—drug delivery systems. Elsevier, New York (2015)

    Google Scholar 

  26. Kim, K., Murray, J., Selvapalam, N., Ko, Y. H., Hwang, I.: Cucurbiturils: syntheses, structures and properties. In: Cucurbiturils: Chemistry, Supramolecular Chemistry and Applications. World Scientific, Press, Singapore, 2018

  27. Das, D., Assaf, K.I., Nau, W.M.: Applications of cucurbiturils in medicinal chemistry and chemical biology. Front. Chem. 7, 619 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gadde, S., Batchelor, E.K., Kaifer, A.E.: Electrochemistry of redox active centres encapsulated by non-covalent methods. Aust. J. Chem. 63, 184–194 (2010)

    CAS  Google Scholar 

  29. Ahmadian, N., Mehrnejad, F., Amininasab, M.: Molecular insight into the interaction between camptothecin and acyclic cucurbit[4]urils as efficient nanocontainers in comparison with cucurbit[7]uril: molecular docking and molecular dynamics simulation. J. Chem. Inf. Model. 60, 1791–1803 (2020)

    CAS  PubMed  Google Scholar 

  30. Albdallah, S.K., Assaf, K.I., Bodoor, K., Al-Sakhen, N.A., Malhis, L.D., Alhmaideen, A.I., El-Barghouthi, M.I.: Cucurbit[7]uril inclusion complexes with benzimidazole derivatives: a computational study. J. Solut. Chem. 47, 1768–1778 (2018)

    CAS  Google Scholar 

  31. Villarroel-Lecourt, G., Carrasco-Carvajal, J., Andrade-Villalobos, F., So-lís-Egaña, F., Martín, I.M.-S., Robinson-Duggon, J., Fuentealba, D.: Encapsulation of chemotherapeutic drug melphalan in cucurbit[7]uril: effects on its alkylating activity, hydrolysis and cytotoxicity. ACS Omega 3, 8337–8343 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Suliman, F.O., Varghese, B.: Inclusion complexes of pantoprazole with β-cyclodextrin and cucurbit[7]uril: experimental and molecular modeling study. J. Incl. Phenom. Macrocycl. Chem. 91, 179–188 (2018)

    CAS  Google Scholar 

  33. Jorgensen, W.L., Maxwell, D.S., Tirado-Rives, J.: Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc. 118, 11225–11236 (1996)

    CAS  Google Scholar 

  34. Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeersch, T., Zurek, E., Hutchison, G.R.: Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminf. 4, 17 (2012)

    CAS  Google Scholar 

  35. Kim, J., Jung, I.-S., Kim, S.-Y., Lee, E., Kang, J.-K., Sakamoto, S., Yamaguchi, K., Kim, K.: New cucurbituril homologues: Syntheses, isolation, characterization, and X-ray crystal structures of cucurbit[n]uril (n = 5, 7, and 8). J. Am. Chem. Soc. 122, 540–541 (2000)

    CAS  Google Scholar 

  36. Seidel, R.W., Koleva, B.B.: β-cyclodextrin 1041-hydrate. Acta Crystallogr. E65, o3162–o3163 (2009)

    Google Scholar 

  37. Neese, F.: ORCA—An Ab Initio, DFT and Semiempirical SCF-MO Package. Max Planck Institut für Strahlenchemie, Mülheim (2010)

    Google Scholar 

  38. Lu, T., Chen, F.: Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012)

    PubMed  Google Scholar 

  39. Ribeiro, A.A.S.T., Horta, B.A.C., de Alencastro, R.B.: MKTOP: a program for automatic construction of molecular topologies. J. Braz. Chem. Soc. 19, 1433–1435 (2008)

    CAS  Google Scholar 

  40. DeLano, W.L.: The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA (2009)

    Google Scholar 

  41. Berendsen, H.J.C., Postama, J.P.M., Van Gunsteren, W.F.: Intermolecular forces. In: B. Pullman, ed., Reidel, Dordrecht, 1981

  42. Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., DiNola, A., Haak, J.R.: Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684–3690 (1984)

    CAS  Google Scholar 

  43. Bussi, G., Donadio, D., Parrinello, M.: Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007)

    PubMed  Google Scholar 

  44. Berendsen, H.J.C.: Simulating the physical World: Hierarchial Modeling from Quantum Mechanics to Fluid Dynamics. Cambridge University Press, New York (2007)

    Google Scholar 

  45. Deserno, M., Holm, C.: How to mesh up Ewald sums: I: A theoretical and numerical comparison of various particle mesh routines. J. Chem. Phys. 109, 7678–7693 (1998)

    CAS  Google Scholar 

  46. Morse, P.M., Feshbach, H.: Asymptotic Series, Method of Steepest Descent: Methods in Theoretical Physics Part I, pp. 434–443. McGraw-Hill, New York (1953)

    Google Scholar 

  47. Hess, B.: P-LINCS: a parallel linear constraint solver for molecular simulation. J. Chem. Theory Comput. 4, 116–122 (2008)

    CAS  PubMed  Google Scholar 

  48. Berendsen, H.J.C., van der Spoel, D., van Drunen, R.: GROMACS: a message-passing parallel molecular dynamics implementation. Comput. Phys. Comm. 91, 43–56 (1995)

    CAS  Google Scholar 

  49. Hess, B., Kutzner, C., van der Spoel, D., Lindahl, E.: GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput. 4, 435–447 (2008)

    CAS  PubMed  Google Scholar 

  50. Kumar, S., Rosenberg, J.M., Sweden, D., Kolman, R.H.: The weighted histogram analysis method for free energy calcularions on biomolecules: I: The method. J. Comput. Chem. 13, 1011–1021 (1992)

    CAS  Google Scholar 

  51. Hub, J.S., de Groot, B.L., van der Spoel, D.: g_wham—a free weighted histogram analysis implementation including robust error and autocorrelation estimates. J. Chem. Theory Comput. 6, 3713–3720 (2010)

    CAS  Google Scholar 

  52. Priotti, J., Ferreira, M.J.G., Lamas, M.C., Leonardi, D., Salomon, C.J., Nunes, T.G.: First solid-state NMR spectroscopy evaluation of complexes of benznidazole with cyclodextrin derivatives. Carbohyd. Polym. 131, 90–97 (2015)

    CAS  Google Scholar 

  53. Espinosa, Y.R., Galvis-ovallos, F., Rozo, A.M.: Purification of the antichagasic benznidazole from the commercial preparation Rochegan: characterization of inclusion complexes with β-cyclodextrin. J. Cienc. Ing. 10, 32–38 (2018)

    Google Scholar 

  54. Soares-Sobrinho, J.L., de La Roca Soares, M.F., Rolim-Neto, P.J., Torres-Labandeira, J.J.: Physicochemical study of solid-state benznidazole–cyclodextrin complexes. J. Therm. Anal. Cal. 106, 319–325 (2011)

    CAS  Google Scholar 

  55. De Lima, A.A.N., Sobrinho, J.L.S., De Lyra, M.A.M., Dos Santos, F.L.A., Figueirêdo, C.B.M., Neto, P.J.R.: Evaluation of in vitro dissolution of benznidazole and binary mixtures: solid dispersions with hydroxypropylmethylcellulose and β-cyclodextrin inclusion complexes. Int. J. Pharm. Pharm. Sci. 7, 371–375 (2015)

    Google Scholar 

  56. Malaspina, T., Fileti, E., Chaban, V.V.: Peculiar aqueous solubility trend in cucurbiturils unraveled by atomistic simulations. J. Phys. Chem. B 120, 7511–7516 (2016)

    CAS  PubMed  Google Scholar 

  57. Biedermann, F., Uzunova, V.D., Scherman, O.A., Nau, W.M., De Simone, A.: Release of high-energy water as an essential driving force for the high-affinity binding of cucurbit[n]urils. J. Am. Chem. Soc. 134, 15318 (2012)

    CAS  PubMed  Google Scholar 

  58. Venkataramanan, N.S., Suvitha, A., Sahara, R.: Structure, stability, and nature of bonding between high energy water clusters confined inside cucurbituril: A computational study. Comput. Theor. Chem. 1148, 44–45 (2019)

    CAS  Google Scholar 

  59. Grishaeva, T.N., Masliy, A.N., Kuznetsov, A.M.: Water structuring inside the cavities of cucurbit[n]urils (n = 5–8): a quantum-chemical forecast. J. Incl. Phenom. Macrocycl. Chem. 89, 299–313 (2017)

    CAS  Google Scholar 

  60. Pereva, S., Nikolova, V., Angelova, S., Spassov, T., Dudev, T.: Water inside β-cyclodextrin cavity: amount, stability and mechanism of binding. Beilstein J. Org. Chem. 15, 1592–1600 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Mixcoha, E., Campos-Teran, J., Piñeiro, A.: Surface adsorption and bulk aggregation of cyclodextrins by computational molecular dynamics simulations as a function of temperature: α-CD vs β-CD. J. Phys. Chem. B 118, 6999–7011 (2014)

    CAS  PubMed  Google Scholar 

  62. Jana, M., Bandyopadhyay, S.: Hydration properties of α-, β-, and γ-cyclodextrins from molecular dynamics simulations. J. Phys. Chem. B 115, 6347–6357 (2011)

    CAS  PubMed  Google Scholar 

  63. You, W., Tang, Z., Chang, C.A.: Potential mean force from umbrella sampling simulations: what can we learn and what is missed? J. Chem. Theory Comput. 15, 2433–2443 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chadha, R., Jain, D.V.S., Aggarwal, A., Singh, S., Thakur, T.: Binding constants of inclusion complexes of nitroimidazoles with β-cyclodextrins in the absence and presence of PVP. Thermochim. Acta 459, 111–115 (2007)

    CAS  Google Scholar 

  65. Soares-Sobrinho, J.L., Santos, F.L.A., Lyra, M.A.M., Alves, L.D.S., Rolim, L.A., Lima, A.A.N., Nunes, L.C.C., Soares, M.F.R., Rolim-Neto, P.J., Torres-Labandeira, J.J.: Benznidazole drug delivery by binary and multicomponent inclusion complexes using cyclodextrins and polymers. Carbohyd. Polym. 89, 323–330 (2012)

    CAS  Google Scholar 

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Acknowledgements

This research was carried out with the support of the FAPESP (São Paulo Research Foundation) under process number of 2018/19844-8.

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  1. Instituto Federal de Educação, Ciência e Tecnologia de São Paulo, Campus Catanduva, Catanduva, SP, CEP: 15.808-305, Brazil

    Osmair Vital de Oliveira & Rafael Giordano Viegas

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de Oliveira, O.V., Viegas, R.G. Cucurbit[7]uril as a possible nanocarrier for the antichagasic benznidazole: a computational approach. J Incl Phenom Macrocycl Chem 98, 93–103 (2020). https://doi.org/10.1007/s10847-020-01014-w

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