Estudo In Silico do Nilotinibe como Possível Inibidor da Protease Principal Mpro do SARS-CoV-2.

Autores

DOI:

https://doi.org/10.36704/cipraxis.v20i35.9203

Palavras-chave:

Nilotinib, Mpro, SARS-CoV-2, Dinâmica Molecular, Docking Molecular

Resumo

Introdução: A pandemia de COVID-19 destacou a necessidade urgente de identificar novos inibidores da protease Mpro do SARS-CoV-2 para o desenvolvimento de terapias antivirais eficazes. O Nilotinibe surge como um potencial candidato. Inibir a protease Mpro do SARS-CoV-2 é essencial, pois essa enzima é responsável pela clivagem de polipeptídeos virais, necessária para a formação de proteínas maduras e a replicação do vírus. Sem a Mpro, o vírus não pode se replicar nem se espalhar, tornando a inibição dessa protease uma estratégia chave no desenvolvimento de terapias antivirais (ou anti-SARS).

Objetivo: Investigar a eficácia do Nilotinibe como inibidor da Mpro do SARS-CoV-2, comparando seus resultados com os do PAXLOVID®, um fármaco já aprovado para uso emergencial.

Métodos: A pesquisa combinou técnicas de Docking Molecular, análise de perfil ADMET e Simulações de Dinâmica Molecular.   

Resultados: O Nilotinibe apresentou um perfil de interação molecular semelhante ao do PAXLOVID®, com potencial para inibir a Mpro. No entanto, sua maior flexibilidade estrutural pode influenciar a estabilidade e afinidade no sítio ativo. Em termos de toxicidade, o Nilotinibe apresenta riscos elevados, incluindo hepatotoxicidade, neurotoxicidade, carcinogenicidade e imunotoxicidade, enquanto o PAXLOVID® é neurotóxico. Além disso, o Nilotinibe possui maior potencial de interações medicamentosas devido à inibição de múltiplas enzimas do citocromo P450. Apesar dessas diferenças, ele pode ser uma alternativa viável, especialmente em casos de resistência ao PAXLOVID®.

Conclusão: Os achados indicam que o Nilotinibe possui características promissoras como candidato inibidor da Mpro do SARS-CoV-2, abrindo caminho para novas abordagens terapêuticas contra a COVID-19. O estudo sugere que o Nilotinibe pode complementar os tratamentos atuais, contribuindo para a diversificação das opções terapêuticas disponíveis.

Biografia do Autor

MARCUS VINÍCIUS HUNGARO FARIA, Universidade Federal Fluminense

É 2º Tenente da Força Aérea Brasileira, na área de Magistério em Química do Ensino Médio (MQM). Atua como professor de Química no Colégio Militar do Rio de Janeiro (Exército). Atualmente, é doutorando em Química pela Universidade Federal Fluminense (UFF), onde desenvolve pesquisa focada no planejamento racional de inibidores contra o vírus SARS-CoV-2. É mestre em Química pela Universidade Federal Rural do Rio de Janeiro (UFRRJ) e licenciado em Química pela mesma instituição. Possui experiência em Modelagem Molecular, incluindo Docking e Dinâmica Molecular, além de Metodologias Inovadoras no Ensino de Química.

RAPHAEL SALLES FERREIRA SILVA, COLÉGIO MILITAR DO RIO DE JANEIRO

É farmacêutico pela Universidade Federal do Rio de Janeiro (UFRJ) e licenciado em Química, além de especialista em Farmácia Clínica. Realizou pós-doutorado em modelagem molecular pelo Instituto Militar de Engenharia (IME). Atuou como professor no Instituto Federal do Rio de Janeiro (IFRJ) entre 2011 e 2023, e atualmente leciona no Colégio Militar do Rio de Janeiro. Tem experiência em Síntese Orgânica, Química de Produtos Naturais e Modelagem Molecular aplicada à Química Medicinal.

CARLOS MAURÍCIO RABELLO SANT'ANNA, Universidade Federal Rural do Rio de Janeiro

É professor titular na Universidade Federal Rural do Rio de Janeiro (UFRRJ). É químico com mestrado em Ciência e Tecnologia de Polímeros pela Universidade Federal do Rio de Janeiro (UFRJ) e doutorado em Química Orgânica também pela UFRJ. Desde 2015, atua como professor titular na UFRRJ e é colaborador do Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio-UFRJ). Possui mais de 100 artigos publicados nas áreas de Química Medicinal e Agroquímica. Foi editor convidado de periódicos e lidera um grupo de pesquisa em Modelagem de Compostos Bioativos.

LUCIANO T. COSTA, Universidade Federal Fluminense

É professor associado no Departamento de Físico-Química da Universidade Federal Fluminense (UFF). Possui graduação em Química e Engenharia Química pela Universidade Federal da Bahia (UFBA), com mestrado em Engenharia Química pela mesma instituição e doutorado em Físico-Química pela Universidade de São Paulo (USP). Realizou pós-doutorado em Simulação Computacional na USP e na Uppsala University, na Suécia. É autor de mais de 65 artigos científicos e sócio fundador da empresa InSILICO, que atua em Inteligência Artificial e Química Computacional. Seu trabalho se concentra em Química Verde e no desenvolvimento de Materiais Sustentáveis.

Referências

ABRAHAM, Mark James et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, v. 1, p. 19-25, 2015. DOI: https://doi.org/10.1016/j.softx.2015.06.001. DOI: Acesso em: 19 set. 2024.

ABRUZZESE, Elisabetta; BRECCIA, Massimo; LATAGLIATA, Roberto. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML). BioDrugs, v. 28, p. 17-26, 2014. DOI: https://doi.org/10.1007/s40259-013-0056-z. Acesso em: 30 jun. 2024.

AHMED, Sabbir et al. Molecular docking and dynamics simulation of natural compounds from betel leaves (Piper betle L.) for investigating the potential inhibition of alpha-amylase and alpha-glucosidase of type 2 diabetes. Molecules, v. 27, n. 14, p. 4526, 2022. DOI: https://doi.org/10.3390/molecules27144526. Acesso em: 19 out. 2024.

ARBEL, Ronen et al. Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge. New England Journal of Medicine, v. 387, n. 9, p. 790-798, 2022. DOI: https://doi.org/10.1056/NEJMoa2204919. Acesso em: 17 fev. 2025.

BANERJEE, Souvik et al. Drug repurposing to identify nilotinib as a potential SARS-CoV-2 main protease inhibitor: insights from a computational and in vitro study. Journal of chemical information and modeling, v. 61, n. 11, p. 5469-5483, 2021. DOI: https://doi.org/10.1021/acs.jcim.1c00524. Acesso em: 20 de fev. 2025.

BASSANI, Davide et al. Re-Exploring the Ability of Common Docking Programs to Correctly Reproduce the Binding Modes of Non-Covalent Inhibitors of SARS-CoV-2 Protease Mpro. Pharmaceuticals, v. 15, n. 2, p. 180, 2022. DOI: https://doi.org/10.3390/ph15020180. Acesso em: 30 jun. 2024.

BECKE, Axel D. Density-functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, v. 98, n. 7, p. 5648–5652, 1993. DOI: https://doi.org/10.1063/1.464913. Acesso em: 19 out. 2024.

BERENDSEN, Herman JC et al. Molecular dynamics with coupling to an external bath. The Journal of chemical physics, v. 81, n. 8, p. 3684-3690, 1984. DOI: https://doi.org/10.1063/1.448118

BERENDSEN, Herman JC. Simulating the physical world. Simulating the Physical World, p. 540, 2004.

BERENDSEN, Herman JC; VAN DER SPOEL, David; VAN DRUNEN, Rudi. GROMACS: A message-passing parallel molecular dynamics implementation. Computer physics communications, v. 91, n. 1-3, p. 43-56, 1995. DOI: https://doi.org/10.1016/0010-4655(95)00042-E. Acesso em: 30 jun. 2024.

BIOVIA, Dassault Systèmes. BIOVIA workbook, release 2017; BIOVIA pipeline pilot, release 2017. San Diego: Dassault Systèmes, 2020. Acesso em: 19 out. 2024.

BOSKO, Jaroslaw T.; TODD, B. D.; SADUS, Richard J. Molecular simulation of dendrimers and their mixtures under shear: Comparison of isothermal-isobaric (NpT) and isothermal-isochoric (NVT) ensemble systems. The Journal of chemical physics, v. 123, n. 3, 2005. DOI: https://doi.org/10.1063/1.1946749. Acesso em: 30 jun. 2024.

BRECCIA, Massimo; ALIMENA, Giuliana. Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leukemia research, v. 34, n. 2, p. 129-134, 2010. DOI: https://doi.org/10.1016/j.leukres.2009.08.031. Acesso em: 30 jun. 2024.

BUSSI, Giovanni; DONADIO, Davide; PARRINELLO, Michele. Canonical sampling through velocity rescaling. The Journal of chemical physics, v. 126, n. 1, 2007. DOI: https://doi.org/10.1063/1.2408420. Acesso em: 20 de jul. 2024.

CITARELLA, Andrea et al. Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives. Biomolecules, v. 13, n. 9, p. 1339, 2023. DOI: https://doi.org/10.3390/biom13091339. Acesso em: 27 out. 2024.

CHEN, Nanshan et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The lancet, v. 395, n. 10223, p. 507-513, 2020. DOI: https://doi.org/10.1016/S0140-6736(20)30211-7. Acesso em: 17 de fev. 2025.

DE AZEVEDO, Nathalia et al. Desenvolvimento de um Modelo Preditivo para a Atividade Inibitória de Tiazolopiridinil-ureias sobre a Subunidade B da DNA Girase de Micobactérias por Meio de Descritores Moleculares. Revista Virtual de Química, 2022, 14(6): 1-11. DOI: http://dx.doi.org/10.21577/1984-6835.20220056. Acesso em: 25 de jul. 2024.

DE OLIVEIRA, Osmair Vital et al. Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening. Journal of Biomolecular Structure and Dynamics, v. 39, n. 11, p. 3924-3933, 2021. DOI: https://doi.org/10.1080/07391102.2020.1772885. Acesso em: 20 de jul. 2024.

DELANO, Warren L. et al. Pymol: An open-source molecular graphics tool. CCP4 Newsl. Protein Crystallogr, v. 40, n. 1, p. 82-92, 2002. Acesso em: 20 set. 2024.

DESERNO, Markus; HOLM, Christian. How to mesh up Ewald sums. I. A theoretical and numerical comparison of various particle mesh routines. The Journal of chemical physics, v. 109, n. 18, p. 7678-7693, 1998. DOI: https://doi.org/10.1063/1.477414

DIAS, Raquel; DE AZEVEDO, Jr; WALTER, F. Molecular docking algorithms. Current Drug Targets, v. 9, n. 12, p. 1040-1047, 2008. DOI: 10.2174/138945008786949432. Acesso em: 15 ago. 2024.

ELDRIDGE, Matthew D. et al. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design, v. 11, p. 425-445, 1997. DOI: 10.1023/A:1007996124545. Acesso em: 30 jun. 2024.

EZZAT, Mohammed Oday; ABD RAZIK, Basma M.; SHIHAB, Wurood A. Molecular modelling and theoretical design of novel Nirmatrelvir derivatives as SARS-CoV-2 entry inhibitors. New Materials, Compounds and Applications, 8(2), 178-189, 2024. DOI: 10.62476/nmca82178. Acesso em: 11 out. 2024.

FDA (Food and Drug Administration). (2021). Fact sheet for healthcare providers: Emergency use authorization for Paxlovid. Disponível em: https://www.fda.gov/. Acesso em: 3 set. 2024.

FDA (Food and Drug Administration). (2023). COVID-19 Vaccines and Treatments. Disponível em: https://www.fda.gov/coronavirus. Acesso em: 17 out. 2024.

FOCOSI, Daniele et al. Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics. International Journal of Antimicrobial Agents, v. 61, n. 2, p. 106708, 2023. DOI: https://doi.org/10.1016/j.ijantimicag.2022.106708. Acesso em: 17 fev. 2025.

FRANÇA, Tanos CC et al. A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials. Journal of the Brazilian Chemical Society, v. 15, p. 450-454, 2004. DOI: 10.1590/S0103-50532004000300019. Acesso em: 8 ago. 2024.

FREITAS, Brendan T. et al. Characterization and noncovalent inhibition of the deubiquitinase and deISGylase activity of SARS-CoV-2 papain-like protease. ACS Infectious Diseases, v. 6, n. 8, p. 2099-2109, 2020. DOI: 10.1021/acsinfecdis.0c00168. Acesso em: 16 out. 2024.

FUHRMANS, Marc et al. Effects of bundling on the properties of the SPC water model. Theoretical Chemistry Accounts, v. 125, p. 335-344, 2010. DOI: https://doi.org/10.1007/s00214-009-0590-4. Acesso em: 15 de jun. 2024.

GEHLHAAR, Daniel K. et al. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chemistry & Biology, v. 2, n. 5, p. 317-324, 1995. Acesso em: 25 jul. 2024.

GUEX, Nicolas; PEITSCH, Manuel C. SWISS‐MODEL and the Swiss‐Pdb Viewer: an environment for comparative protein modeling. Electrophoresis, v. 18, n. 15, p. 2714-2723, 1997. DOI: 10.1002/elps.1150181505. Acesso em: 29 set. 2024.

GUTTI, Gopichand et al. In-silico guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for the targeted treatment of COVID-19. Journal of Biomolecular Structure and Dynamics, v. 42, n. 4, p. 1733-1750, 2024. DOI: 10.1080/07391102.2023.2202247. Acesso em: 2 out. 2024.

HANWELL, Marcus D. et al. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of cheminformatics, v. 4, p. 1-17, 2012.

HEHRE, Warren J.; DITCHFIELD, Robert; POPLE, John A. Self-consistent molecular orbital methods. XII. Further extensions of Gaussian-type basis sets for use in molecular orbital studies of organic molecules. The Journal of Chemical Physics, v. 56, n. 5, p. 2257-2261, 1972. DOI: https://doi.org/10.1063/1.1677527. Acesso em: 19 out. 2024.

HESS, Berk et al. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. Journal of chemical theory and computation, v. 4, n. 3, p. 435-447, 2008. DOI: https://doi.org/10.1021/ct700301q. Acesso em: 30 jun. 2024.

JIN, Zhenming et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, v. 582, n. 7811, p. 289-293, 2020. DOI: https://doi.org/10.1038/s41586-020-2223-y. Acesso em: 10 de out. 2024.

JONES, Gareth et al. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology, v. 267, n. 3, p. 727-748, 1997. DOI: https://doi.org/10.1006/jmbi.1996.0897. Acesso em: 12 de set. 2024.

JORGENSEN, William L. et al. Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics, v. 79, n. 2, p. 926-935, 1983. DOI: https://doi.org/10.1063/1.445869. Acesso em: 17 de out. 2024.

KANDWAL, Shubhangi; FAYNE, Darren. Genetic conservation across SARS-CoV-2 non-structural proteins–Insights into possible targets for treatment of future viral outbreaks. Virology, v. 581, p. 97-115, 2023. DOI: https://doi.org/10.1016/j.virol.2023.02.011. Acesso em: 17 de fev. 2025.

KHURANA, Varun et al. Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. Drug Metabolism and Drug Interactions, v. 29, n. 4, p. 249-259, 2014. DOI: https://doi.org/10.1515/dmdi-2014-0014. Acesso em: 14 de ago. 2024.

KHURANA, Varun et al. Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors. Drug Metabolism and Drug Interactions, v. 29, n. 3, p. 179-190, 2014. DOI: https://doi.org/10.1515/dmdi-2013-0062. Acesso em: 10 de jul. 2024.

KINCAID, Joseph RA et al. A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid. Communications Chemistry, v. 5, n. 1, p. 156, 2022. DOI: https://doi.org/10.1038/s42004-022-00758-5. Acesso em: 11 de ago. 2024.

KOULGI, Shruti et al. Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CLpro). Journal of Biomolecular Structure and Dynamics, v. 39, n. 15, p. 5735-5755, 2021. DOI: https://doi.org/10.1080/07391102.2020.1792344. Acesso em: 13 de set. 2024.

LASKOWSKI, Roman A. et al. PDBsum: Structural summaries of PDB entries. Protein Science, v. 27, n. 1, p. 129-134, 2018. DOI: https://doi.org/10.1002/pro.3289. Acesso em: 17 de out. 2024.

LEE, Chengteh; YANG, Weitao; PARR, Robert G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B, v. 37, n. 2, p. 785, 1988. DOI: https://doi.org/10.1103/PhysRevB.37.785. Acesso em: 19 out. 2024.

LEE, Jonathan T. et al. Genetic surveillance of SARS-CoV-2 Mpro reveals high sequence and structural conservation prior to the introduction of protease inhibitor Paxlovid. Mbio, v. 13, n. 4, p. e00869-22, 2022. DOI: https://doi.org/10.1128/mbio.00869-22. Acesso em: 12 de set. 2024.

LEMKUL, J. A. Introductory tutorials for simulating protein dynamics with GROMACS. The Journal of Physical Chemistry B, 2024. DOI: https://doi.org/10.1021/acs.jpcb.4c04901. Acesso em: 19 out. 2024.

LI, Qun et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New England Journal of Medicine, v. 382, n. 13, p. 1199-1207, 2020. DOI: https://doi.org/10.1056%2FNEJMoa2001316. Acesso em: 15 de jun. 2024.

LIPINSKI, Christopher A. et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, v. 64, p. 4-17, 2012. DOI: https://doi.org/10.1016/s0169-409x(00)00129-0. Acesso em: 10 de out. 2024.

LOSCHWITZ, Jennifer et al. Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay. Bioorganic Chemistry, v. 111, p. 104862, 2021. DOI: https://doi.org/10.1016/j.bioorg.2021.104862. Acesso em: 20 de fev. 2025.

LIU, Cynthia et al. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. 2020. ACS pharmacology & translational science, 3(5), 813-834. DOI: https://doi.org/10.1021/acscentsci.0c00272. Acesso em: 10 de jul. 2024.

LIU, Nanxin et al. Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library. International journal of molecular sciences, v. 24, n. 14, p. 11390, 2023. DOI: https://doi.org/10.3390/ijms241411390. Acesso em: 20 de fev. 2025.

LIU, Xiaodong. Transporter-mediated drug-drug interactions and their significance. In: Drug Transporters in Drug Disposition, Effects and Toxicity, p. 241-291, 2019. Acesso em: 17 de out. 2024.

LU, Roujian et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The lancet, v. 395, n. 10224, p. 565-574, 2020. DOI: https://doi.org/10.1016/S0140-6736(20)30251-8. Acesso em: 17 de fev. 2025.

MACKERELL JR, Alexander D.; BANAVALI, Nilesh; FOLOPPE, Nicolas. Development and current status of the CHARMM force field for nucleic acids. Biopolymers: Original Research on Biomolecules, v. 56, n. 4, p. 257-265, 2000. DOI: https://doi.org/10.1002/1097-0282(2000)56:4%3C257::AID-BIP10029%3E3.0.CO;2-W. Acesso em: 15 de jun. 2024.

MAHASE, Elisabeth. Covid-19: Pfizer’s Paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ, 2021. DOI: https://doi.org/10.1136/bmj.n2713. Acesso em: 12 de set. 2024.

MANLEY, Paul W. et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, v. 1804, n. 3, p. 445-453, 2010. DOI: https://doi.org/10.1016/j.bbapap.2009.11.008. Acesso em: 14 de ago. 2024.

MESECAR, A. D. et al. A taxonomically-driven approach to development of potent, broad-spectrum inhibitors of coronavirus main protease including SARS-CoV-2 (COVID-19). Be Publ, v. 10, 2020. DOI: http://doi.org/10.2210/pdb6w63/pdb. Acesso em: 10 de jul. 2024.

MOLAVI, Zahra et al. Identification of FDA approved drugs against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease (3CLpro), drug repurposing approach. Biomedicine & Pharmacotherapy, v. 138, p. 111544, 2021. DOI: https://doi.org/10.1016/j.biopha.2021.111544. Acesso em: 20 de fev. 2025.

MOOIJ, Wijnand TM; VERDONK, Marcel L. General and targeted statistical potentials for protein–ligand interactions. Proteins: Structure, Function, and Bioinformatics, v. 61, n. 2, p. 272-287, 2005. DOI: https://doi.org/10.1002/prot.20588. Acesso em: 11 de ago. 2024.

MORSE, Philip McCord; FESHBACH, Herman. Methods of theoretical physics. Technology Press, 1946.

NAIK, Vankudavath Raju et al. Remdesivir (GS-5734) as a therapeutic option of 2019-nCOV main protease–in silico approach. Journal of Biomolecular Structure and Dynamics, v. 39, n. 13, p. 4701-4714, 2021. DOI: https://doi.org/10.1080/07391102.2020.1781694. Acesso em: 15 de jun. 2024.

NEESE, F. ORCA–an Ab Initio, DFT and Semiempirical SCF-MO Package. D-45470 Mülheim/Ruhr: Max Planck Institute for Bioinorganic Chemistry. Version 4.2.1, 2010. Acesso em: 17 de out. 2024.

NEESE, Frank. Software update: the ORCA program system, version 4.0. Wiley Interdisciplinary Reviews: Computational Molecular Science, v. 8, n. 1, p. e1327, 2018. DOI: https://doi.org/10.1002/wcms.1327. Acesso em: 30 jun. 2024.

NGUYEN, Hoang Linh et al. Remdesivir strongly binds to both RNA-dependent RNA polymerase and main protease of SARS-CoV-2: Evidence from molecular simulations. The Journal of Physical Chemistry B, v. 124, n. 50, p. 11337-11348, 2020. DOI: https://doi.org/10.1021/acs.jpcb.0c07312. Acesso em: 10 de out. 2024.

NOVAK, Jurica et al. Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking. Journal of Biomolecular Structure and Dynamics, v. 40, n. 19, p. 9347-9360, 2022. DOI: https://doi.org/10.1080/07391102.2021.1927845. Acesso em: 20 de fev. 2025.

NOVICK, Paul A. et al. SWEETLEAD: an in silico database of approved drugs, regulated chemicals, and herbal isolates for computer-aided drug discovery. PloS One, v. 8, n. 11, p. e79568, 2013. DOI: https://doi.org/10.1371/journal.pone.0079568. Acesso em: 12 de set. 2024.

OH, Kwang Jin; DENG, Yuefan. An efficient parallel implementation of the smooth particle mesh Ewald method for molecular dynamics simulations. Computer Physics Communications, v. 177, n. 5, p. 426-431, 2007. DOI: 10.1016/j.cpc.2007.05.005. Acesso em: 12 jul. 2024.

PICCIRILLO, Erika; AMARAL, Antonia Tavares do. Virtual screening of bioactive compounds: concepts and applications. Química Nova, v. 41, p. 662-677, 2018. DOI: https://doi.org/10.21577/0100-4042.20170210. Acesso em: 14 de ago. 2024.

PRONK, Sander et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, v. 29, n. 7, p. 845-854, 2013. DOI: https://doi.org/10.1093/bioinformatics/btt055. Acesso em: 15 de jun. 2024.

QIAO, Zhen et al. The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus. Bioorganic Chemistry, v. 117, p. 105455, 2021. DOI: https://doi.org/10.1016/j.bioorg.2021.105455. Acesso em: 30 jun. 2024.

RIZZO-VALENTE, V. S.; OLIVEIRA, J. S.; VIZZONI, V. F. XEC: international spread of a new sublineage of Omicron SARS-CoV-2. Authorea Preprints, 2024. DOI: 10.22541/au.172873324.41905753/v1. Acesso em: 10 de jul. 2024.

ROCHA, Gerd B. et al. Rm1: A reparameterization of am1 for h, c, n, o, p, s, f, cl, br, and i. Journal of Computational Chemistry, 2006, 27(10): 1101-1111. DOI: https://doi.org/10.1002/jcc.20425. Acesso em: 12 de jul. 2024.

SANTOS, Samuel JM; VALENTINI, Antoninho. In silico investigation of Komaroviquinone as a potential inhibitor of SARS-CoV-2 main protease (Mpro): Molecular docking, molecular dynamics, and QM/MM approaches. Journal of Molecular Graphics and Modelling, 2024, 126: 108662. DOI: https://doi.org/10.1016/j.jmgm.2023.108662. Acesso em: 15 de jul. 2024.

SCHWEDE, Torsten et al. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Research, 2003, 31(13): 3381-3385. DOI: https://doi.org/10.1093/nar/gkg520. Acesso em: 20 de jul. 2024.

SHAQRA, Ala M. et al. Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance. Nature Communications, 2022, 13(1): 3556. DOI: https://doi.org/10.1038/s41467-022-31210-w. Acesso em: 25 de jul. 2024.

SHRESTHA, Sundar S. et al. Estimation of coronavirus disease 2019 hospitalization costs from a large electronic administrative discharge database, March 2020–July 2021. In: Open forum infectious diseases. US: Oxford University Press, 2021. p. ofab561. DOI: https://doi.org/10.1093/ofid/ofab561. Acesso em: 17 de fev. 2025.

SILVA, Raphael SF et al. In silico studies of semi-synthetic benzo [a] phenazines as inhibitors of dihydrofolate reductase from Plasmodium falciparum. Journal of Molecular Structure, v. 1237, p. 130404, 2021.

SILVA, Raphael SF et al. In silico study of the interaction of phenazines with tuberculostatic activity with known molecular targets of Mycobacterium tuberculosis. Results in Chemistry, v. 6, p. 101094, 2023.

SILVA, Raphael SF et al. INVESTIGATING CHOLAGOGUE AND CHOLERETIC ACTIVITY OF PEUMUS BOLDUS. Química Nova, v. 48, n. 3, p. e-20250091, 2025. DOI: http://dx.doi.org/10.21577/0100-4042.20250091. Acesso em: 17 de fev. 2025.

SMITH, J. et al. Guidelines for Second-Line Therapies in Clinical Practice. Journal of Clinical Medicine, 2023, 12(1): 100-110. DOI: https://doi.org/10.3390/jcm12010001. Acesso em: 1 de ago. 2024.

SOUSA DA SILVA, Alan W.; VRANKEN, Wim F. ACPYPE-Antechamber python parser interface. BMC Research Notes, 2012, 5: 1-8. DOI: https://doi.org/10.1186/1756-0500-5-367. Acesso em: 5 de ago. 2024.

SUN, Le-Yun et al. Ebsulfur and Ebselen as highly potent scaffolds for the development of potential SARS-CoV-2 antivirals. Bioorganic Chemistry, v. 112, p. 104889, 2021. DOI: https://doi.org/10.1016/j.bioorg.2021.104889. Acesso em: 30 jun. 2024.

VAN DER SPOEL, David et al. GROMACS: fast, flexible, and free. Journal of Computational Chemistry, 2005, 26(16): 1701-1718. DOI: https://doi.org/10.1002/jcc.20291. Acesso em: 10 de ago. 2024.

VARDHAN, Seshu; SAHOO, Suban K. In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Computers in Biology and Medicine, 2020, 124: 103936. DOI: https://doi.org/10.1016/j.compbiomed.2020.103936. Acesso em: 15 de ago. 2024.

WANG, Fenghua et al. Structure of main protease from human coronavirus NL63: insights for wide spectrum anti-coronavirus drug design. Scientific reports, v. 6, n. 1, p. 22677, 2016. DOI: https://doi.org/10.1038/srep22677. Acesso em: 20 de ago. 2024.

WANG, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell, v. 181, n. 4, p. 894-904.e9, 14 maio 2020. DOI: https://doi.org/10.1016/j.cell.2020.03.045. Epub em: 9 abr. 2020. PMID: 32275855; PMCID: PMC7144619. Acesso em: 20 out. 2024.

WEIGEND, Florian; AHLRICHS, Reinhart. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Physical Chemistry Chemical Physics, v. 7, n. 18, p. 3297-3305, 2005. Acesso em: 19 out. 2024.

WELLINGTON, K. W. Understanding cancer and the anticancer activities of naphthoquinones – a review. RSC Advances, v. 5, n. 26, p. 20309-20338, 2015. DOI: https://doi.org/10.1039/C4RA13547D. Acesso em: 19 out. 2024.

WHO (World Health Organization). COVID-19 Weekly Epidemiological Update. 2023. Disponível em: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---20-september-2023. Acesso em: 25 de set. 2024.

WHO (World Health Organization). Tracking SARS-CoV-2 variants. 2023. Disponível em: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/. Acesso em: 17 de out. 2024.

WU, Fan et al. A new coronavirus associated with human respiratory disease in China. Nature, 2020, 579(7798): 265-269. DOI: https://doi.org/10.1038/s41586-020-2008-3. Acesso em: 30 de out. 2024.

XUE, Xiaoyu et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design. Journal of Virology, 2008, 82(5): 2515-2527. DOI: https://doi.org/10.1128/jvi.02114-07. Acesso em: 5 de nov. 2024.

YAGHI, Rasha M. et al. An Investigation of Nirmatrelvir (Paxlovid) Resistance in SARS-CoV-2 Mpro. ACS Bio & Med Chem Au, 2024. DOI: https://doi.org/10.1021/acsbiomedchemau.4c00045. Acesso em: 10 de nov. 2024.

ZHANG, Deng-hai et al. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. Journal of Integrative Medicine, 2020, 18(2): 152-158. DOI: https://doi.org/10.1016/j.joim.2020.02.005. Acesso em: 15 de nov. 2024.

ZHANG, Linlin et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 2020, 368(6489): 409-412. DOI: https://doi.org/10.1126/science.abb3405. Acesso em: 20 de nov. 2024.

ZHOU, Peng et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798): 270-273. DOI: https://doi.org/10.1038/s41586-020-2012-7. Acesso em: 25 de nov. 2024.

ZHOU, Shilin et al. SARS-CoV-2 E protein: Pathogenesis and potential therapeutic development. Biomedicine & Pharmacotherapy, v. 159, p. 114242, 2023. DOI: https://doi.org/10.1016/j.biopha.2023.114242. Acesso em: 22 de fev. 2025.

ZHU, Na et al. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine, 2020, 382(8): 727-733. DOI: https://doi.org/10.1056/NEJMoa2001017. Acesso em: 30 de nov. 2024

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2025-04-15

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HUNGARO FARIA, M. V., SALLES FERREIRA SILVA, R., RABELLO SANT’ANNA, C. M., & TAVARES DA COSTA, L. (2025). Estudo In Silico do Nilotinibe como Possível Inibidor da Protease Principal Mpro do SARS-CoV-2. Ciência ET Praxis, 20(35), 141–164. https://doi.org/10.36704/cipraxis.v20i35.9203

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v. 20 n. 35 (2025): Edição 01/2025

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