Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this s...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2024.1336001/full |
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| author | João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha Renato Araújo da Costa Renato Araújo da Costa Andreia do Socorro Silva da Costa Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Anderson José Bahia Gomes Alencar Kolinski Machado Solange Binotto Fagan Davi do Socorro Barros Brasil Davi do Socorro Barros Brasil Anderson Henrique Lima e Lima Anderson Henrique Lima e Lima |
| author_facet | João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha Renato Araújo da Costa Renato Araújo da Costa Andreia do Socorro Silva da Costa Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Anderson José Bahia Gomes Alencar Kolinski Machado Solange Binotto Fagan Davi do Socorro Barros Brasil Davi do Socorro Barros Brasil Anderson Henrique Lima e Lima Anderson Henrique Lima e Lima |
| author_sort | João Augusto Pereira da Rocha |
| collection | DOAJ |
| description | SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski’s rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results. |
| first_indexed | 2024-03-07T23:07:33Z |
| format | Article |
| id | doaj.art-e1376e60d9e94817bf4a54612d7297f2 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-03-07T23:07:33Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-e1376e60d9e94817bf4a54612d7297f22024-02-22T04:37:57ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462024-02-011210.3389/fchem.2024.13360011336001Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulationJoão Augusto Pereira da Rocha0João Augusto Pereira da Rocha1João Augusto Pereira da Rocha2João Augusto Pereira da Rocha3Renato Araújo da Costa4Renato Araújo da Costa5Andreia do Socorro Silva da Costa6Elaine Cristina Medeiros da Rocha7Elaine Cristina Medeiros da Rocha8Elaine Cristina Medeiros da Rocha9Elaine Cristina Medeiros da Rocha10Anderson José Bahia Gomes11Alencar Kolinski Machado12Solange Binotto Fagan13Davi do Socorro Barros Brasil14Davi do Socorro Barros Brasil15Anderson Henrique Lima e Lima16Anderson Henrique Lima e Lima17Laboratory of Modeling and Computational Chemistry, Federal Institute of Education, Science and Technology of Paraná (IFPA) Campus Bragança, Bragança, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, BrazilLaboratory of Biosolutions and Bioplastics of the Amazon, Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém, BrazilGraduate Program in Chemistry, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, BrazilLaboratory of Biosolutions and Bioplastics of the Amazon, Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém, BrazilLaboratory of Molecular Biology, Evolution and Microbiology, Federal Institute of Education Science and Technology of Paraná (IFPA) Campus Abaetetuba, Abaetetuba, BrazilLaboratory of Biosolutions and Bioplastics of the Amazon, Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém, BrazilLaboratory of Modeling and Computational Chemistry, Federal Institute of Education, Science and Technology of Paraná (IFPA) Campus Bragança, Bragança, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, BrazilLaboratory of Biosolutions and Bioplastics of the Amazon, Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém, BrazilGraduate Program in Chemistry, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, BrazilLaboratory of Molecular Biology, Evolution and Microbiology, Federal Institute of Education Science and Technology of Paraná (IFPA) Campus Abaetetuba, Abaetetuba, BrazilGraduate Program in Nanosciences, Franciscana University, Santa Maria, BrazilGraduate Program in Nanosciences, Franciscana University, Santa Maria, BrazilLaboratory of Biosolutions and Bioplastics of the Amazon, Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém, BrazilGraduate Program in Chemistry, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, BrazilGraduate Program in Chemistry, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, BrazilSARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski’s rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results.https://www.frontiersin.org/articles/10.3389/fchem.2024.1336001/fullSARS-CoV-2main proteaseflavonoidsdrug-likenessnatural productsmolecular docking |
| spellingShingle | João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha João Augusto Pereira da Rocha Renato Araújo da Costa Renato Araújo da Costa Andreia do Socorro Silva da Costa Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Elaine Cristina Medeiros da Rocha Anderson José Bahia Gomes Alencar Kolinski Machado Solange Binotto Fagan Davi do Socorro Barros Brasil Davi do Socorro Barros Brasil Anderson Henrique Lima e Lima Anderson Henrique Lima e Lima Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation Frontiers in Chemistry SARS-CoV-2 main protease flavonoids drug-likeness natural products molecular docking |
| title | Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation |
| title_full | Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation |
| title_fullStr | Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation |
| title_full_unstemmed | Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation |
| title_short | Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation |
| title_sort | harnessing brazilian biodiversity database identification of flavonoids as potential inhibitors of sars cov 2 main protease using computational approaches and all atom molecular dynamics simulation |
| topic | SARS-CoV-2 main protease flavonoids drug-likeness natural products molecular docking |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2024.1336001/full |
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