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.
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