Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition
| العنوان: | Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition |
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| المؤلفون: | Ibrahim, Mahmoud A. A., Abdelrahman, Alaa H. M., Atia, Mohamed A. M., Mohamed, Tarik A., Moustafa, Mahmoud F., Hakami, Abdulrahim R., Khalifa, Shaden A. M., Alhumaydhi, Fahad A., Alrumaihi, Faris, Abidi, Syed Hani, Allemailem, Khaled S., Efferth, Thomas, Soliman, Mahmoud E., Pare, Paul W., El-Seedi, Hesham R., Hegazy, Mohamed-Elamir F. |
| المصدر: | Marine Drugs. 19(7) |
| مصطلحات موضوعية: | genus Sarcophyton, cembranoid diterpenes metabolites, SARS-CoV-2 main protease, molecular docking, molecular dynamics, reactome |
| الوصف: | The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (M-pro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target M-pro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 M-pro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as M-pro inhibitors with Delta G(binding) < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against M-pro than darunavir with Delta G(binding) values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2. |
| وصف الملف: | electronic |
| URL الوصول: | https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-451561 https://doi.org/10.3390/md19070391 https://uu.diva-portal.org/smash/get/diva2:1594749/FULLTEXT01.pdf |
| قاعدة البيانات: | SwePub |
| تدمد: | 16603397 |
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| DOI: | 10.3390/md19070391 |