Hostname: page-component-848d4c4894-ttngx Total loading time: 0 Render date: 2024-05-30T03:28:59.914Z Has data issue: false hasContentIssue false
  • English
  • Français

Oligopeptidase B and B2: comparative modelling and virtual screening as searching tools for new antileishmanial compounds

Published online by Cambridge University Press:  29 December 2016

ANA CAROLINA R. SODERO Open the ORCID record for ANA CAROLINA R. SODERO [Opens in a new window] ,
ANA CAROLINA G. O. DOS SANTOS ,
JULIANA F. R. E MELLO ,
JÉSSICA B. DE JESUS ,
ALESSANDRA M. T. DE SOUZA ,
MARIA ISABEL C. RODRIGUES ,
SALVATORE G. DE SIMONE ,
CARLOS R. RODRIGUES  and
HERBERT L. DE MATOS GUEDES
ANA CAROLINA R. SODERO*
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
ANA CAROLINA G. O. DOS SANTOS
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
JULIANA F. R. E MELLO
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
JÉSSICA B. DE JESUS
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
ALESSANDRA M. T. DE SOUZA
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
MARIA ISABEL C. RODRIGUES
Affiliation:
Centro de Desenvolvimento Tecnológico em Saúde (CDTS)/Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN), 21045-900 Rio de Janeiro, RJ, Brazil
SALVATORE G. DE SIMONE
Affiliation:
Centro de Desenvolvimento Tecnológico em Saúde (CDTS)/Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN), 21045-900 Rio de Janeiro, RJ, Brazil
CARLOS R. RODRIGUES
Affiliation:
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil
HERBERT L. DE MATOS GUEDES*
Affiliation:
Grupo de Imunologia e Vacinologia, Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil Núcleo Multidisciplinar de Pesquisa UFRJ – Xerém em Biologia (NUMPEX-BIO), Polo Avançado de Xerém – Universidade Federal do Rio de Janeiro, 25245-390 Duque de Caxias, RJ, Brazil
*
*Corresponding authors: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil. E-mail: acrsodero@pharma.ufrj.br and Grupo de Imunologia e Vacinologia, Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil. E-mail: herbert@biof.ufrj.br
*Corresponding authors: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR), Departamento de Fármacos e Medicamentos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, 21941-599, Brazil. E-mail: acrsodero@pharma.ufrj.br and Grupo de Imunologia e Vacinologia, Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil. E-mail: herbert@biof.ufrj.br
Get access Rights & Permissions [Opens in a new window]

Summary

Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.

Keywords

Leishmaniasisoligopeptidasevirtual screeningdocking
Type
Research Article
Information
Parasitology , Volume 144 , Issue 4 , April 2017 , pp. 536 - 545
Check for updates
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W. and Lipman, D. J. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research 25, 3389–3402.Google Scholar
Andrade, M. A., O'Donoghue, S. I. and Rost, B. (1998). Adaptation of protein surfaces to subcellular location. Journal of Molecular Biology 276, 517–525.CrossRefGoogle ScholarPubMed
Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research 28, 235–242.Google Scholar
Bowie, J. U., Luthy, R. and Eisenberg, D. (1991). A method to identify protein sequences that fold into a known three-dimensional structure. Science 253, 164–170.CrossRefGoogle ScholarPubMed
Caler, E.V., Avalos, S.V., Haynes, P.A., Andrews, N.W. and Burleigh, B.A. (1998). Oligopeptidase B-dependent signaling mediates host cell invasion by Trypanosoma cruzi . The EMBO Journal 17, 4975–4986.Google Scholar
Cerqueira, N. M., Gesto, D., Oliveira, E. F., Santos-Martins, D., Bras, N. F., Sousa, S. F., Fernandes, P. A. and Ramos, M. J. (2015). Receptor-based virtual screening protocol for drug discovery. Archives of Biochemistry and Biophysics 582, 56–67.Google Scholar
de Matos Guedes, H. L., Carneiro, M. P., Gomes, D. C., Rossi-Bergmanmn, B. and Giovanni de Simone, S. (2007). Oligopeptidase B from L. amazonensis: molecular cloning, gene expression analysis and molecular model. Parasitology Research 101, 853–863.Google Scholar
de Matos Guedes, H. L. M., Carvalho, R. S. N., Gomes, D. C. O., Rossi-Bergmann, B. and De-Simone, S. G. (2008). Oligopeptidase B-2 from Leishmania amazonensis with an unusual C-terminal extension. Acta Parasitologica 53, 197–204.CrossRefGoogle Scholar
Dill, K. A. and MacCallum, J. L. (2012). The protein-folding problem, 50 years on. Science 338, 1042–1046.Google Scholar
Genestra, M., Guedes-Silva, D., Souza, W. J. S., Cysne-Finkelstein, L., Soares-Bezerra, R. J., Monteiro, F. P. and Leon, L. L. (2006). Nitric oxide synthase (NOS) characterization in Leishmania amazonensis axenic amastigotes. Archives of Medical Research 37, 328–333.Google Scholar
Goyal, S., Grover, S., Dhanjal, J.K., Goyal, M., Tyagi, C., Chacko, S. and Grover, A. (2014). Mechanistic insights into mode of actions of novel oligopeptidase B inhibitors for combating leishmaniasis. Journal of Molecular Modeling 20, 2099.Google Scholar
Grimaldi, G. Jr. and McMahan-Pratt, D. (1991). Leishmaniasis and its etiologic agents in the New World: an overview. Progress in Clinical Parasitology 2, 73–118.Google Scholar
Irwin, J. J. and Shoichet, B. K. (2005). ZINC – a free database of commercially available compounds for virtual screening. Journal of Chemical Information and Modeling 45, 177–182.Google Scholar
Irwin, J. J., Shoichet, B. K., Mysinger, M. M., Huang, N., Colizzi, F., Wassam, P. and Cao, Y. (2009). Automated docking screens: a feasibility study. Journal of Medicinal Chemistry 52, 5712–5720.Google Scholar
Ivens, A. C., Peacock, C. S., Worthey, E. A., Murphy, L., Aggarwal, G., Berriman, M., Sisk, E., Rajandream, M. A., Adlem, E., Aert, R., Anupama, A., Apostolou, Z., Attipoe, P., Bason, N., Bauser, C., Beck, A., Beverley, S. M., Bianchettin, G., Borzym, K., Bothe, G., Bruschi, C. V., Collins, M., Cadag, E., Ciarloni, L., Clayton, C., Coulson, R. M., Cronin, A., Cruz, A. K., Davies, R. M., De Gaudenzi, J. et al. (2005). The genome of the kinetoplastid parasite, Leishmania major . Science 309, 436–442.Google Scholar
Kaur, P. K., Dinesh, N., Soumya, N., Babu, N. K. and Singh, S. (2012). Identification and characterization of a novel ribose 5-phosphate isomerase B from Leishmania donovani . Biochemical and Biophysical Research Communications 421, 51–56.Google Scholar
Killick-Kendrick, R. (1999). The biology and control of phlebotomine sand flies. Clinics in Dermatology 17, 279–289.Google Scholar
Laskowski, R.A., MacArthur, M.W., Moss, D.S. and Thornton, J.M. (1993). PROCHECK - a program to check the stereochemical quality of protein structures. Journal of Applied Crystallography 26, 283–291.Google Scholar
Libusova, L., Sulimenko, T., Sulimenko, V., Hozak, P. and Draber, P. (2004). Gamma-tubulin in Leishmania: cell cycle-dependent changes in subcellular localization and heterogeneity of its isoforms. Experimental Cell Research 295, 375–386.Google Scholar
Luthy, R., Bowie, J. U. and Eisenberg, D. (1992). Assessment of protein models with three-dimensional profiles. Nature 356, 83–85.Google Scholar
McLuskey, K., Paterson, N. G., Bland, N. D., Isaacs, N. W. and Mottram, J. C. (2010). Crystal structure of Leishmania major oligopeptidase B gives insight into the enzymatic properties of a trypanosomatid virulence factor. Journal of Biological Chemistry 285, 39249–39259.Google Scholar
Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K. and Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry 19, 1639–1662.Google Scholar
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. and Olson, A. J. (2009). AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30, 2785–2791.Google Scholar
Morty, R. E., Lonsdale-Eccles, J. D., Morehead, J., Caler, E. V., Mentele, R., Auerswald, E. A., Coetzer, T. H., Andrews, N. W. and Burleigh, B. A. (1999). Oligopeptidase B from Trypanosoma brucei, a new member of an emerging subgroup of serine oligopeptidases. Journal of Biological Chemistry 274, 26149–26156.Google Scholar
Mottram, J. C., North, M.J., Barry, J.D. and Coombs, G.H. (1989). A cysteine proteinase cDNA from Trypanosoma brucei predicts an enzyme with an unusual C-terminal extension. FEBS Letters 258, 211–215.CrossRefGoogle ScholarPubMed
Munday, J. C., McLuskey, K., Brown, E., Coombs, G. H. and Mottram, J. C. (2011). Oligopeptidase B deficient mutants of Leishmania major . Molecular & Biochemical Parasitology 175, 49–57.Google Scholar
Notredame, C. (2010). Computing multiple sequence/structure alignments with the T-coffee package. Current Protocols in Bioinformatics Chapter 3, Unit 3, 8, 1–25.Google Scholar
Padmanabhan, P. K., Mukherjee, A., Singh, S., Chattopadhyaya, S., Gowri, V. S., Myler, P. J., Srinivasan, N. and Madhubala, R. (2005). Glyoxalase I from Leishmania donovani: a potential target for anti-parasite drug. Biochemical and Biophysical Research Communications 337, 1237–1248.Google Scholar
Polgar, L. (2002). The prolyl oligopeptidase family. Cellular and Molecular Life Sciences 59, 349–362.Google Scholar
Pontius, J., Richelle, J. and Wodak, S. J. (1996). Deviations from standard atomic volumes as a quality measure for protein crystal structures. Journal of Molecular Biology 264, 121–136.Google Scholar
Reguera, R. M., Tekwani, B. L. and Balana-Fouce, R. (2005). Polyamine transport in parasites: a potential target for new antiparasitic drug development. Comparative Biochemistry and Physiology C – Toxicology & Pharmacology 140, 151–164.Google Scholar
Sali, A. and Blundell, T. L. (1993). Comparative protein modeling by satisfaction of spatial restraints. Journal of Molecular Biology 234, 779–815.Google Scholar
Santos, D. O., Coutinho, C. E., Madeira, M. F., Bottino, C. G., Vieira, R. T., Nascimento, S. B., Bernardino, A., Bourguignon, S. C., Corte-Real, S., Pinho, R. T., Rodrigues, C. R. and Castro, H. C. (2008). Leishmaniasis treatment – a challenge that remains: a review. Parasitology Research 103, 1–10.Google Scholar
Singh, B. and Sundar, S. (2012). Leishmaniasis: vaccine candidates and perspectives. Vaccine 30, 3834–3842.Google Scholar
Stauffert, I., Paulini, H., Steinmann, U., Sippel, H. and Estler, C. J. (1990). Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines. Mutation Research 245, 93–98.Google Scholar
Suda, H., Aoyagi, T., Hamada, M., Takeuchi, T. and Umezawa, H. (1972). Antipain, a new protease inhibitor isolated from actinomycetes. Journal of Antibiotics (Tokyo) 25, 263–266.CrossRefGoogle ScholarPubMed
UniProt, C. (2012). Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Research 40, D71–D75.Google Scholar
Vermelho, A.B., Supuran, C.T., Cardoso, V., Menezes, D., Silva, J.R.d.A., Ferreira, J.L.P., Amaral, A.C.F. and Rodrigues, I.A. (2014). Leishmaniasis: possible new strategies for treatment. In Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment (ed. Claborn, D.), pp. 351–376. InTech, DOI: 10.5772/57388. Available from: http://www.intechopen.com/books/leishmaniasis-trends-in-epidemiology-diagnosis-and-treatment/leishmaniasis-possible-new-strategies-for-treatment Google Scholar
Williams, R.A., Kelly, S.M., Mottram, J.C. and Coombs, G.H. (2003). 3-Mercaptopyruvate sulfurtransferase of Leishmania contains an unusual C-terminal extension and is involved in thioredoxin and antioxidant metabolism. Journal of Biological Chemistry 278, 1480–1486.Google Scholar
Wong, J.Y., Harrop, S.A., Day, S.R. and Brindley, P.J. (1997). Schistosomes express two forms of cathepsin D. Biochimica et Biophysica Acta 1338, 156–160.Google Scholar
World Health Organization, WHO (2015). “Leishmaniasis.” Retrieved 26.02.2016, 2015, from http://www.who.int/topics/leishmaniasis/en Google Scholar