Triagem virtual e ancoragem molecular de estruturas com potencial inibidor da glicoproteína do ebolavírus
DOI:
https://doi.org/10.33448/rsd-v11i2.26034Palavras-chave:
EBOV GP; Triagem Virtual; Ancoragem molecular.Resumo
O ebola é uma doença causada por vírus do gênero ebolavírus que ocasionam febre hemorrágica com alta mortalidade humana. Os sintomas da infecção compreendem febre, dor de cabeça, dores nas articulações, diarreia, vômito e dor de estômago. Infelizmente, ainda não existe tratamento eficaz para esta doença. Este trabalho teve como objetivo realizar a triagem virtual de candidatos com potencial de inibição da EBOV GP baseada em farmacóforos de 4 estruturas da literatura. Os candidatos selecionados passaram por analise ADME e posteriormente cálculos de HOMO, LUMO e mapa de potencial eletrostático. 50 estruturas foram obtidas e após seleção com bases nas suas características ADME somente 4 candidatos foram escolhidos. No processo de ancoragem molecular a estrutura que apresentou a melhor energia de ligação foi a ZINC12 com -18.59 kJ.mol-1 e constante de inibição enzimática Ki igual a 555.9 µM. Este resultado é fundamental, pois subsidiará outras pesquisas tais como estudos de in vitro, ou mesmo aplicação em amostras reais.
Referências
Anders, E., Koch, R., & Freunscht, P. (1993). Optimization and application of lithium parameters for PM3. Journal of computational chemistry, 14(11), 1301-1312.
Antal Jr, M. J., Leesomboon, T., Mok, W. S., & Richards, G. N. (1991). Mechanism of formation of 2-furaldehyde from D-xylose. Carbohydrate Research, 217, 71-85.
Arooj, M., Sakkiah, S., Kim, S., Arulalapperumal, V., & Lee, K. W. (2013). A combination of receptor-based pharmacophore modeling & QM techniques for identification of human chymase inhibitors. PLoS One, 8(4), e63030.
Ault, B. S. (2018). Matrix Isolation Spectroscopic Studies: Thermal and Soft Photochemical Bimolecular Reactions. In Frontiers and Advances in Molecular Spectroscopy (pp. 667-712). Elsevier.
Azam, S. S., & Abbasi, S. W. (2013). Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines. Theoretical Biology and Medical Modelling, 10(1), 1-16.
Azeredo, F. J., Uchôa, F. D. T., & Costa, T. D. (2009). Papel da glicoproteína-P na farmacocinética e nas interações medicamentosas. Rev Bras Farm, 90(4), 321-326.
Baize, S., Pannetier, D., Oestereich, L., Rieger, T., Koivogui, L., Magassouba, N. F., ... & Günther, S. (2014). Emergence of Zaire Ebola virus disease in Guinea. New England Journal of Medicine, 371(15), 1418-1425.
Balimane, P. V., Chong, S., & Morrison, R. A. (2000). Current methodologies used for evaluation of intestinal permeability and absorption. Journal of pharmacological and toxicological methods, 44(1), 301-312.
Barreiro, E. J., & Fraga, C. A. M. (2014). Química Medicinal-: As bases moleculares da ação dos fármacos. Artmed Editora.
Bastos, R. S., Sousa, C. S., Oliveira, J. S., da Silva, M. H. V., Lima, F. D. C. A., & Rocha, J. A. (2020). Prospecção de Proteínas do Novo Coronavírus Covid-2019 e Potencial da Bioinformática na Busca de Novas Drogas Promissoras. Cadernos de Prospecção, 13(2 COVID-19), 347.
Beaulieu, D., & Ohemeng, K. A. (1999). Patents on bacterial tRNA synthetase inhibitors: January 1996 to March 1999. Expert Opinion on Therapeutic Patents, 9(8), 1021-1028.
Beeching, N. J., Fenech, M., & Houlihan, C. F. (2014). Ebola virus disease. BMJ 349: g7348.
Benet, L. Z., & Hoener, B. A. (2002). Changes in plasma protein binding have little clinical relevance. Clinical Pharmacology & Therapeutics, 71(3), 115-121.
Berman, H. M., Battistuz, T., Bhat, T. N., Bluhm, W. F., Bourne, P. E., Burkhardt, K., ... & Zardecki, C. (2002). The protein data bank. Acta Crystallographica Section D: Biological Crystallography, 58(6), 899-907.
Bissantz, C., Folkers, G., & Rognan, D. (2000). Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. Journal of medicinal chemistry, 43(25), 4759-4767.
Braga, E. J., Corpe, B. T., Marinho, M. M., & Marinho, E. S. (2016). Molecular electrostatic potential surface, HOMO–LUMO, and computational analysis of synthetic drug Rilpivirine. Int. J. Sci. Eng. Res, 7(7), 315-319.
Brehm, M. A., Bortell, R., Verma, M., Shultz, L. D., & Greiner, D. L. (2016). Humanized mice in translational immunology. Translational immunology: mechanisms and pharmacological approaches, 285-326.
Breman, J. G., Heymann, D. L., Lloyd, G., McCormick, J. B., Miatudila, M., Murphy, F. A., ... & Johnson, K. M. (2016). Discovery and description of Ebola Zaire virus in 1976 and relevance to the West African epidemic during 2013–2016. The Journal of infectious diseases, 214(suppl_3), S93-S101.
Case, D. A., Cheatham III, T. E., Darden, T., Gohlke, H., Luo, R., Merz Jr, K. M., ... & Woods, R. J. (2005). The Amber biomolecular simulation programs. Journal of computational chemistry, 26(16), 1668-1688.
Castillo-Garit, J. A., Marrero-Ponce, Y., Torrens, F., & García-Domenech, R. (2008). Estimation of ADME properties in drug discovery: predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices. Journal of pharmaceutical sciences, 97(5), 1946-1976.
Cruz, J. V., Serafim, R. B., da Silva, G. M., Giuliatti, S., Rosa, J. M., Neto, M. F. A., ... & Santos, C. B. (2018). Computational design of new protein kinase 2 inhibitors for the treatment of inflammatory diseases using QSAR, pharmacophore-structure-based virtual screening, and molecular dynamics. Journal of molecular modeling, 24(9), 1-16.
Csizmadia, P. (1999). MarvinSketch and MarvinView: molecule applets for the World Wide Web.
Da Silva Costa, J., da Silva Lopes Costa, K., Cruz, J. V., da Silva Ramos, R., Silva, L. B., Do Socorro Barros Brasil, D., ... & da Cruz Macedo, W. J. (2018). Virtual screening and statistical analysis in the design of new caffeine analogues molecules with potential epithelial anticancer activity. Current pharmaceutical design, 24(5), 576-594.
De Oliveira, A. M. (2018). Introdução à modelagem Molecular para Química, Engenharia e Biomédicas: fundamentos e exercícios. Appris Editora e Livraria Eireli-ME.
Desai, C. (2016). Meyler's side effects of drugs: The international encyclopedia of adverse drug reactions and interactions. Indian Journal of Pharmacology, 48(2), 224.
Dezani, T. M., Dezani, A. B., da Silva Junior, J. B., & dos Reis Serra, C. H. (2016). Single-Pass Intestinal Perfusion (SPIP) and prediction of fraction absorbed and permeability in humans: A study with antiretroviral drugs. European Journal of Pharmaceutics and Biopharmaceutics, 104, 131-139.
Dos Santos, K. L., Cruz, J. N., Silva, L. B., Ramos, R. S., Neto, M. F., Lobato, C. C., ... & Santos, C. B. (2020). Identification of novel chemical entities for adenosine receptor type 2a using molecular modeling approaches. Molecules, 25(5), 1245.
Feldmann, H., & Geisbert, T. W. (2011). Ebola haemorrhagic fever. The Lancet, 377(9768), 849-862.
Gasteiger, J., & Marsili, M. (1980). Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron, 36(22), 3219-3228.
Gujjula, K. R. (2008). Prediction and comparison of hiv-1 protease inhibitor binding energies by various molecular docking methods (Doctoral dissertation).
Irvine, J. D., Takahashi, L., Lockhart, K., Cheong, J., Tolan, J. W., Selick, H. E., & Grove, J. R. (1999). MDCK (Madin–Darby canine kidney) cells: a tool for membrane permeability screening. Journal of pharmaceutical sciences, 88(1), 28-33.
Jacoby, H. I. (2017). Gastric Emptying.
Johns, P. (2014). Clinical Neuroscience E-Book. Elsevier Health Sciences.
Khabbaz, R., Bell, B. P., Schuchat, A., Ostroff, S. M., Moseley, R., Levitt, A., & Hughes, J. M. (2015). Emerging and reemerging infectious disease threats. Mandell, Douglas, and Bennett's principles and practice of infectious diseases, 158.
Koes, D. R. (2018). The Pharmit backend: A computer systems approach to enabling interactive online drug discovery. IBM journal of research and development, 62(6), 3-1.
La Regina, G., Gatti, V., Piscitelli, F., & Silvestri, R. (2011). Open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N-aryl hydrazones. ACS combinatorial science, 13(1), 2-6.
Larkin, P. (2017). Infrared and Raman spectroscopy: principles and spectral interpretation. Elsevier.
Lee, S. K., Lee, I. H., Kim, H. J., Chang, G. S., Chung, J. E., & No, K. T. (2003). The PreADME Approach: Web-based program for rapid prediction of physico-chemical, drug absorption and drug-like properties. EuroQSAR 2002 Designing Drugs and Crop Protectants: processes, problems and solutions, 2003, 418-420.
Loprinzi, C. L., Barton, D. L., & Qin, R. (2011). Nonestrogenic management of hot flashes. Journal of Clinical Oncology, 29(29), 3842-3846.
Ma, X. L., Chen, C., & Yang, J. (2005). Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacologica Sinica, 26(4), 500-512.
Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., & Simmerling, C. (2015). ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. Journal of chemical theory and computation, 11(8), 3696-3713.
Mali, S. N., & Chaudhari, H. K. (2019). Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking, pharmacophore and 3D-QSAR. SAR and QSAR in Environmental Research, 30(3), 161-180.
Mamman, A. S., Lee, J. M., Kim, Y. C., Hwang, I. T., Park, N. J., Hwang, Y. K., ... & Hwang, J. S. (2008). Furfural: Hemicellulose/xylosederived biochemical. Biofuels, Bioproducts and Biorefining: Innovation for a sustainable economy, 2(5), 438-454.
Marcolin, M. A., Cantarelli, M. D. G., & Garcia Junior, M. (2004). Interações farmacológicas entre medicações clínicas e psiquiátricas. Archives of Clinical Psychiatry (São Paulo), 31, 70-81.
Matusiak, A., Lewkowski, J., Rychter, P., & Biczak, R. (2013). Phytotoxicity of new furan-derived aminophosphonic acids, N-aryl furaldimines and 5-nitrofuraldimine. Journal of agricultural and food chemistry, 61(32), 7673-7678.
Mendonça, M. C. P. (2016). Óxido de grafeno e sistema nervoso central= avaliação dos efeitos na barreira hematoencefálica e perfil nanotoxicológico= Graphene oxide and central nervous system: evaluation of effects on blood brain barrier and nanotoxicological profile.
Moda, T. L. (2007). Desenvolvimento de modelos in silico de propriedades de ADME para triagem de novos candidatos a fármacos. São Paulo, Brazil: Universidade de São Paulo.
Mohanazadeh, F., & Aghvami, M. (2007). Ionic liquids as reagent and reaction medium: Preparation of alkyl aryl ethers. Monatshefte für Chemie-Chemical Monthly, 138(1), 47-49.
Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of computational chemistry, 19(14), 1639-1662.
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.
Mukund, V., Behera, S. K., Alam, A., & Nagaraju, G. P. (2019). Molecular docking analysis of nuclear factor-κB and genistein interaction in the context of breast cancer. Bioinformation, 15(1), 11.
Naz, A., Bano, K., Bano, F., Ghafoor, N. A., & Akhtar, N. (2009). Conformational analysis (geometry optimization) of nucleosidic antitumor antibiotic showdomycin by Arguslab 4 software. Pakistan journal of pharmaceutical sciences, 22(1).
Nimlos, M. R., Qian, X., Davis, M., Himmel, M. E., & Johnson, D. K. (2006). Energetics of xylose decomposition as determined using quantum mechanics modeling. The Journal of Physical Chemistry A, 110(42), 11824-11838.
Normant Annales de Chimie (Cachan, France), 1942 , vol. <11> 17, p. 335,346
Nova, A., & Maseras, F. (2013). Enantioselective Synthesis. In Comprehensive Inorganic Chemistry II (Second Edition): From Elements to Applications (pp. 807-831).
Orellana, M., & Guajardo, V. (2004). Actividad del citocromo P450 y su alteración en diversas patologías. Revista médica de Chile, 132(1), 85-94.
Ortiz, D. M., Carranza, R. C., Ramírez, A. M. D., & Mejía, A. V. (2012). Modulación de la expresión de enzimas del citocromo P450 hepáticas durante las etapas fetal y pediátrica. Revista de Educación Bioquímica, 31(2), 60-71.
Oso, B. J., Adeoye, A. O., & Olaoye, I. F. (2020). Pharmacoinformatics and hypothetical studies on allicin, curcumin, and gingerol as potential candidates against COVID-19-associated proteases. Journal of Biomolecular Structure and Dynamics, 1-12.
Ostroff, D., McDade, J., LeDuc, J., & Hughes, J. M. (2005). Emerging and reemerging infectious disease threats. Principles and practice of infectious disease. Philadelphia, Elsevier Churchill Livingstone, 173-192.
Ouakki, M., Galai, M., Rbaa, M., Abousalem, A. S., Lakhrissi, B., Rifi, E. H., & Cherkaoui, M. (2019). Quantum chemical and experimental evaluation of the inhibitory action of two imidazole derivatives on mild steel corrosion in sulphuric acid medium. Heliyon, 5(11), e02759.
Pahutski, T. F., Lahm, G. P., Kar, M., & Ahmad, O. K. (2015). U.S. Patent No. 9,113,631. Washington, DC: U.S. Patent and Trademark Office.
Parrot, M., Tajmouati, H., da Silva, V. B. R., Atwood, B. R., Fourcade, R., Gasthon-Mathé, Y., ... & Perron, Q. (2021). Integrating synthetic accessibility with AI-based generative drug design.
Pereira, D. H., La Porta, F. A., Santiago, R. T., Garcia, D. R., & Ramalho, T. C. (2016). Novas perspectivas sobre o papel dos orbitais moleculares de fronteira no estudo da reatividade química: uma revisão. Revista Virtual de Química, 8(2), 425-453.
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of computational chemistry, 25(13), 1605-1612.
Plewczynski, D., Łaźniewski, M., Augustyniak, R., & Ginalski, K. (2011). Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database. Journal of computational chemistry, 32(4), 742-755.
Price, D. J., & Brooks III, C. L. (2004). A modified TIP3P water potential for simulation with Ewald summation. The Journal of chemical physics, 121(20), 10096-10103.
Rajapaksha, H., Perera, B. T., Meepage, J., Perera, R. T., & Dissanayake, C. (2020). Mitigate the cytokine storm due to the severe COVID-19: A computational investigation of possible allosteric inhibitory actions on IL-6R and IL-1R using selected phytochemicals. European Journal of Chemistry, 11(4), 351-363.
Ramalingam, S., Babu, P. D. S., Periandy, S., & Fereyduni, E. (2011). Vibrational investigation, molecular orbital studies and molecular electrostatic potential map analysis on 3-chlorobenzoic acid using hybrid computational calculations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 84(1), 210-220.
Ramírez, D., & Caballero, J. (2018). Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data?. Molecules, 23(5), 1038.
Reeve, E. C. (Ed.). (2014). Encyclopedia of genetics. Routledge.
Ren, J., Zhao, Y., Fry, E. E., & Stuart, D. I. (2018). Target identification and mode of action of four chemically divergent drugs against ebolavirus infection. Journal of medicinal chemistry, 61(3), 724-733.
Richman, D. D., & Nathanson, N. (2016). Antiviral therapy. In Viral pathogenesis (pp. 271-287). Academic Press.
Rocha, J. A., Rego, N. C., Carvalho, B. T., Silva, F. I., Sousa, J. A., Ramos, R. M., ... & Lima, F. C. (2018). Computational quantum chemistry, molecular docking, and ADMET predictions of imidazole alkaloids of Pilocarpus microphyllus with schistosomicidal properties. PloS one, 13(6), e0198476.
Roe, D. R., & Cheatham III, T. E. (2013). PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. Journal of chemical theory and computation, 9(7), 3084-3095.
Rothman, R. B., Baumann, M. H., Prisinzano, T. E., & Newman, A. H. (2008). Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochemical pharmacology, 75(1), 2-16.
Rougeron, V., Feldmann, H., Grard, G., Becker, S., & Leroy, E. M. (2015). Ebola and Marburg haemorrhagic fever. Journal of Clinical Virology, 64, 111-119.
Sambuy, Y., De Angelis, I., Ranaldi, G., Scarino, M. L., Stammati, A., & Zucco, F. (2005). The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell biology and toxicology, 21(1), 1-26.
Santos, J. L. (2007). Avaliação da atividade mutagênica da talidomida pelo teste de ames. Revista Eletrônica de Farmácia, 4(2).
Schneidman-Duhovny, D., Dror, O., Inbar, Y., Nussinov, R., & Wolfson, H. J. (2008). PharmaGist: a webserver for ligand-based pharmacophore detection. Nucleic acids research, 36(suppl_2), W223-W228.
Singh, K., Sharma, P. K., Dhawan, S. N., & Singh, S. P. (2005). Synthesis and characterisation of some novel indeno [1, 2-c] pyrazoles. Journal of Chemical Research, 2005(8), 526-529.
Souza, R. L. D. (2015). Aplicação da técnica de ancoragem molecular na otimização do fármaco hipoglicemiante metformina. Centr Uni Luter Palm. Palmas.
Studio, D. (2008). Discovery Studio. Accelrys [2.1].
Towner, J. S., Pourrut, X., Albariño, C. G., Nkogue, C. N., Bird, B. H., Grard, G., ... & Leroy, E. M. (2007). Marburg virus infection detected in a common African bat. PloS one, 2(8), e764.
Van Harten, J. (1993). Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clinical pharmacokinetics, 24(3), 203-220.
Vieira, J. B., Braga, F. S., Lobato, C. C., Santos, C. F., Costa, J. S., Bittencourt, J. A. H., ... & Santos, C. B. R. (2014). A QSAR, pharmacokinetic and toxicological study of new artemisinin compounds with anticancer activity. Molecules, 19(8), 10670-10697.
Wadapurkar, R. M., Shilpa, M. D., Katti, A. K. S., & Sulochana, M. B. (2018). In silico drug design for Staphylococcus aureus and development of host-pathogen interaction network. Informatics in Medicine Unlocked, 10, 58-70.
Wang, B., & Merz, K. M. (2006). A fast QM/MM (quantum mechanical/molecular mechanical) approach to calculate nuclear magnetic resonance chemical shifts for macromolecules. Journal of chemical theory and computation, 2(1), 209-215.
Wenthur, C. J., Gentry, P. R., Mathews, T. P., & Lindsley, C. W. (2014). Drugs for allosteric sites on receptors. Annual review of pharmacology and toxicology, 54, 165-184.
Wermuth, C. G., Villoutreix, B., Grisoni, S., Olivier, A., & Rocher, J. P. (2015). Strategies in the search for new lead compounds or original working hypotheses. In The practice of medicinal chemistry (pp. 73-99). Academic Press.
Wishart, D. S., Feunang, Y. D., Guo, A. C., Lo, E. J., Marcu, A., Grant, J. R., ... & Wilson, M. (2018). DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic acids research, 46(D1), D1074-D1082.
Wold, E. A., Chen, J., Cunningham, K. A., & Zhou, J. (2018). Allosteric modulation of class A GPCRs: targets, agents, and emerging concepts. Journal of medicinal chemistry, 62(1), 88-127.
WORLD HEALTH ORGANIZATION. (2020). Doença do vírus Ebola. Retrieved December 9, 2021, from https://www.who.int/news-room/fact-sheets/detail/ebola-virus-disease
Yamashita, S., Furubayashi, T., Kataoka, M., Sakane, T., Sezaki, H., & Tokuda, H. (2000). Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. European journal of pharmaceutical sciences, 10(3), 195-204.
Yan, A., Wang, Z., & Cai, Z. (2008). Prediction of human intestinal absorption by GA feature selection and support vector machine regression. International journal of molecular sciences, 9(10), 1961-1976.
Yang, C. Y. (2015). Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method. PloS one, 10(2), e0118671.
Yang, J. F., Wang, F., Chen, Y. Z., Hao, G. F., & Yang, G. F. (2020). LARMD: integration of bioinformatic resources to profile ligand-driven protein dynamics with a case on the activation of estrogen receptor. Briefings in Bioinformatics, 21(6), 2206-2218.
Yokoi, K., Yada, H., Yoshimoto, D., Hakuno, D., Miyazaki, K., & Adachi, T. (2013). A case of drug‐induced interstitial pneumonia caused by repeated exposure to bepridil. Journal of Arrhythmia, 29(1), 39-42.
Zeitsch, K. J. (2000). The chemistry and technology of furfural and its many by-products. Elsevier.
Zhang, M., Zhang, S., Zhang, G., Chen, F., & Cheng, J. (2011). Palladium/NHC-catalyzed oxidative esterification of aldehydes with phenols. Tetrahedron Letters, 52(19), 2480-2483.
Downloads
Publicado
Como Citar
Edição
Seção
Licença
Copyright (c) 2022 Maria de Lourdes de Aguiar Silva Ferreira; Ruan Sousa Bastos; Lúcio Rocha de Lima; Edielson dos Santos Barbosa; Ionara Nayana Gomes Passos; Cleydson Breno Rodrigues dos Santos; Janilson Lima Souza; Ulisses Alves do Rego
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
Autores que publicam nesta revista concordam com os seguintes termos:
1) Autores mantém os direitos autorais e concedem à revista o direito de primeira publicação, com o trabalho simultaneamente licenciado sob a Licença Creative Commons Attribution que permite o compartilhamento do trabalho com reconhecimento da autoria e publicação inicial nesta revista.
2) Autores têm autorização para assumir contratos adicionais separadamente, para distribuição não-exclusiva da versão do trabalho publicada nesta revista (ex.: publicar em repositório institucional ou como capítulo de livro), com reconhecimento de autoria e publicação inicial nesta revista.
3) Autores têm permissão e são estimulados a publicar e distribuir seu trabalho online (ex.: em repositórios institucionais ou na sua página pessoal) a qualquer ponto antes ou durante o processo editorial, já que isso pode gerar alterações produtivas, bem como aumentar o impacto e a citação do trabalho publicado.
