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El-Demerdash, Amr 
ORCID: https://orcid.org/0000-0001-6459-2955, Al-Karmalawy, Ahmed A., Abdel-Aziz, Tarek Mohamed, Elhady, Sameh S., Darwish, Khaled M. and Hassan, Ahmed H. E.
(2021)
Investigating the structure-activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors.
RSC Advances, 11 (50).
pp. 31339-31363.
ISSN 2046-2069
Abstract
Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on the worldwide finance, healthcare system, and even daily life. Even with the introduction of different preventive vaccines, there is still a dire need for effective antiviral therapeutics. Nature has been considered as the historical trove of drug discovery and development, particularly in cases of worldwide crises. Herein, a comprehensive in silico investigation of a highly focused chemical library of 34 pederin-structurally related marine compounds, belonging to four polyketides families, was initiated against the SARS-CoV-2 main protease, Mpro, being the key replicating element of the virus and main target in many drugs development programs. Two of the most potent SARS-CoV-2 Mpro co-crystallized inhibitors, O6K and N3, were added to the tested database as reference standards. Through molecular docking simulation, promising compounds including Pederin (1), Dihydro-onnamide A (11), Onnamide C (14), Pseudo-onnamide A (17), and Theopederin G (29) have been identified from different families based on their superior ligand-protein energies and relevant binding profiles with the key Mpro pocket residues. Thermodynamic behaviors of the identified compounds were investigated through 200 ns all-atom molecular dynamics simulation illustrating their significant stability and pocket accommodation. Furthermore, structural activity preferentiality was identified for the pederin-based marine compounds highlighting the importance of the terminal guanidine and cyclic hemiacetal linker, and the length of the sidechain. Our findings highlight the challenges of targeting SARS-CoV-2 Mpro as well as recommending further in vitro and in vivo studies regarding the examined marine products either alone or in combination paving the way for promising lead molecules.
| Item Type: | Article |
|---|---|
| Additional Information: | Publisher Copyright: © 2021 The Royal Society of Chemistry. |
| Uncontrolled Keywords: | chemistry(all),chemical engineering(all),sdg 3 - good health and well-being,sdg 14 - life below water ,/dk/atira/pure/subjectarea/asjc/1600 |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 02 Aug 2024 14:30 |
| Last Modified: | 25 Sep 2024 17:59 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96114 |
| DOI: | 10.1039/d1ra05817g |
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