Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds
As a follow-up to our teamwork’s former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 i...
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | Journal of Chemistry |
| Online Access: | http://dx.doi.org/10.1155/2024/5084553 |
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| author | Ibrahim H. Eissa Abdulrahman M. Saleh Sara T. Al-Rashood Abdul-Aziz M. M. El-Attar Ahmed M. Metwaly |
| author_facet | Ibrahim H. Eissa Abdulrahman M. Saleh Sara T. Al-Rashood Abdul-Aziz M. M. El-Attar Ahmed M. Metwaly |
| author_sort | Ibrahim H. Eissa |
| collection | DOAJ |
| description | As a follow-up to our teamwork’s former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 inhibitors targeting the main protease (PDB ID: 5R84), Mpro. The compounds were named in the midst of 3009 FDA and clinically approved compounds employing a multistaged in silico method. A molecular fingerprints study with GWS, the cocrystallized ligand of the Mpro, indicated the resemblance of 150 candidates. Consequently, a structure similarity experiment disclosed the best twenty-nine analogous. Then, molecular docking studies were done against the Mpro active site and showed the binding of the best compounds. Next, a 3D-pharmacophore study confirmed the obtained results for the eight compounds by exhibiting relative fit values of more than 90% (except for 68, 74%, and 2384, 83%). Levobupivacaine (2840) showed the most accurate docking and pharmacophore scores and was picked for further MD simulations experiments (RMSD, RMSF, Rg, SASA, and H-H bonding) over 100 ns. The MD simulations results revealed the accurate binding as well as the optimum dynamics of the Mpro-levobupivacaine complex. Finally, MM-PBSA studies were conducted and indicated the favorable bonding of the Mpro-levobupivacaine complex with a free energy value of −235 kJ/mol. The fulfilled outcomes hold out hope of beating COVID-19 through more in vitro and in vivo research for the named compounds. |
| format | Article |
| id | doaj-art-5bbc0fa8f04a42a4addd5572504b7209 |
| institution | Kabale University |
| issn | 2090-9071 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Chemistry |
| spelling | doaj-art-5bbc0fa8f04a42a4addd5572504b72092025-02-03T06:14:54ZengWileyJournal of Chemistry2090-90712024-01-01202410.1155/2024/5084553Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved CompoundsIbrahim H. Eissa0Abdulrahman M. Saleh1Sara T. Al-Rashood2Abdul-Aziz M. M. El-Attar3Ahmed M. Metwaly4Pharmaceutical Medicinal Chemistry & Drug Design DepartmentPharmaceutical Medicinal Chemistry & Drug Design DepartmentDepartment of Pharmaceutical ChemistryPharmaceutical Analytical Chemistry DepartmentPharmacognosy and Medicinal Plants DepartmentAs a follow-up to our teamwork’s former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 inhibitors targeting the main protease (PDB ID: 5R84), Mpro. The compounds were named in the midst of 3009 FDA and clinically approved compounds employing a multistaged in silico method. A molecular fingerprints study with GWS, the cocrystallized ligand of the Mpro, indicated the resemblance of 150 candidates. Consequently, a structure similarity experiment disclosed the best twenty-nine analogous. Then, molecular docking studies were done against the Mpro active site and showed the binding of the best compounds. Next, a 3D-pharmacophore study confirmed the obtained results for the eight compounds by exhibiting relative fit values of more than 90% (except for 68, 74%, and 2384, 83%). Levobupivacaine (2840) showed the most accurate docking and pharmacophore scores and was picked for further MD simulations experiments (RMSD, RMSF, Rg, SASA, and H-H bonding) over 100 ns. The MD simulations results revealed the accurate binding as well as the optimum dynamics of the Mpro-levobupivacaine complex. Finally, MM-PBSA studies were conducted and indicated the favorable bonding of the Mpro-levobupivacaine complex with a free energy value of −235 kJ/mol. The fulfilled outcomes hold out hope of beating COVID-19 through more in vitro and in vivo research for the named compounds.http://dx.doi.org/10.1155/2024/5084553 |
| spellingShingle | Ibrahim H. Eissa Abdulrahman M. Saleh Sara T. Al-Rashood Abdul-Aziz M. M. El-Attar Ahmed M. Metwaly Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds Journal of Chemistry |
| title | Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds |
| title_full | Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds |
| title_fullStr | Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds |
| title_full_unstemmed | Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds |
| title_short | Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds |
| title_sort | multistaged in silico discovery of the best sars cov 2 main protease inhibitors amongst 3009 clinical and fda approved compounds |
| url | http://dx.doi.org/10.1155/2024/5084553 |
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