In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies
Aristote Matondo,1 Washington Dendera,2 Bienfait Kabuyaya Isamura,1– 3 Koto-te-Nyiwa Ngbolua,4 Hilaire VS Mambo,1 Mayaliwa Muzomwe,1 Virima Mudogo1 1Department of Chemistry, University of Kinshasa, Kinshasa, Democratic Republic of the Congo; 2Department of Chemistry, Rhodes University, Makhanda, Eas...
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Dove Medical Press
2022-08-01
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| Series: | Advances and Applications in Bioinformatics and Chemistry |
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| Online Access: | https://www.dovepress.com/in-silico-drug-repurposing-of-anticancer-drug-5-fu-and-analogues-again-peer-reviewed-fulltext-article-AABC |
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| author | Matondo A Dendera W Isamura BK Ngbolua KTN Mambo HVS Muzomwe M Mudogo V |
| author_facet | Matondo A Dendera W Isamura BK Ngbolua KTN Mambo HVS Muzomwe M Mudogo V |
| author_sort | Matondo A |
| collection | DOAJ |
| description | Aristote Matondo,1 Washington Dendera,2 Bienfait Kabuyaya Isamura,1– 3 Koto-te-Nyiwa Ngbolua,4 Hilaire VS Mambo,1 Mayaliwa Muzomwe,1 Virima Mudogo1 1Department of Chemistry, University of Kinshasa, Kinshasa, Democratic Republic of the Congo; 2Department of Chemistry, Rhodes University, Makhanda, Eastern Cape, South Africa; 3Research Center for Theoretical Chemistry and Physics in Central Africa, Department of Chemistry, University of Kinshasa, Kinshasa, Democratic Republic of the Congo; 4Department of Biology, University of Kinshasa, Kinshasa, Democratic Republic of the CongoCorrespondence: Aristote Matondo, Email aristote.matondo@unikin.ac.cdBackground: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro).Material and Methods: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals.Results and Discussion: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained.Conclusion: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.Keywords: drug repurposing, 5-fluorouracil, SARS-CoV-2, molecular docking, molecular dynamics simulation, ADMET |
| first_indexed | 2024-04-13T18:36:10Z |
| format | Article |
| id | doaj.art-648a5079cf114951acec4869cef2f9b3 |
| institution | Directory Open Access Journal |
| issn | 1178-6949 |
| language | English |
| last_indexed | 2024-04-13T18:36:10Z |
| publishDate | 2022-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Advances and Applications in Bioinformatics and Chemistry |
| spelling | doaj.art-648a5079cf114951acec4869cef2f9b32022-12-22T02:34:52ZengDove Medical PressAdvances and Applications in Bioinformatics and Chemistry1178-69492022-08-01Volume 15597777388In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity StudiesMatondo ADendera WIsamura BKNgbolua KTNMambo HVSMuzomwe MMudogo VAristote Matondo,1 Washington Dendera,2 Bienfait Kabuyaya Isamura,1– 3 Koto-te-Nyiwa Ngbolua,4 Hilaire VS Mambo,1 Mayaliwa Muzomwe,1 Virima Mudogo1 1Department of Chemistry, University of Kinshasa, Kinshasa, Democratic Republic of the Congo; 2Department of Chemistry, Rhodes University, Makhanda, Eastern Cape, South Africa; 3Research Center for Theoretical Chemistry and Physics in Central Africa, Department of Chemistry, University of Kinshasa, Kinshasa, Democratic Republic of the Congo; 4Department of Biology, University of Kinshasa, Kinshasa, Democratic Republic of the CongoCorrespondence: Aristote Matondo, Email aristote.matondo@unikin.ac.cdBackground: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro).Material and Methods: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals.Results and Discussion: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained.Conclusion: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.Keywords: drug repurposing, 5-fluorouracil, SARS-CoV-2, molecular docking, molecular dynamics simulation, ADMEThttps://www.dovepress.com/in-silico-drug-repurposing-of-anticancer-drug-5-fu-and-analogues-again-peer-reviewed-fulltext-article-AABCdrug repurposing5-fluorouracilsars-cov-2molecular dockingmolecular dynamics simulationadmet |
| spellingShingle | Matondo A Dendera W Isamura BK Ngbolua KTN Mambo HVS Muzomwe M Mudogo V In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies Advances and Applications in Bioinformatics and Chemistry drug repurposing 5-fluorouracil sars-cov-2 molecular docking molecular dynamics simulation admet |
| title | In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies |
| title_full | In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies |
| title_fullStr | In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies |
| title_full_unstemmed | In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies |
| title_short | In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies |
| title_sort | in silico drug repurposing of anticancer drug 5 fu and analogues against sars cov 2 main protease molecular docking molecular dynamics simulation pharmacokinetics and chemical reactivity studies |
| topic | drug repurposing 5-fluorouracil sars-cov-2 molecular docking molecular dynamics simulation admet |
| url | https://www.dovepress.com/in-silico-drug-repurposing-of-anticancer-drug-5-fu-and-analogues-again-peer-reviewed-fulltext-article-AABC |
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