The lack of any effective cure for the infectious
COVID-19 disease has created a sense of urgency and motivated the search for effective
antiviral drugs. Abyssomicins are actinomyces-derived spirotetronates
polyketides antibiotics known for their promising antibacterial, antitumor, and
antiviral activities. In this study, computational approaches were used to investigate the binding mechanism and the inhibitory ability of 38 abyssomicins against the main
protease (Mpro) and the spike
protein receptor-binding domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The results identified abyssomicins C, J, W, atrop-O-benzyl
abyssomicin C, and atrop-O-benzyl desmethyl
abyssomicin C as the most potential inhibitors of Mpro and RBD with binding energy ranges between -8.1 and -9.9 kcal mol-1; and between -6.9 and -8.2 kcal mol-1, respectively. Further analyses of physicochemical properties and
drug-likeness suggested that all selected active abyssomicins, with the exception of
abyssomicin J, obeyed Lipinski's rule of five. The stability of
protein-
ligand complexes was confirmed by performing molecular dynamics simulation for 100 ns and evaluating parameters such as such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg),
solvent accessible surface area (SASA), total number of contacts, and secondary structure. Prime/MM-GBSA (Molecular Mechanics-General Born Surface Area) and principal component analysis (PCA) analyses also confirmed the stable nature of
protein-
ligand complexes. Overall, the results showed that the studied abyssomicins have significant interactions with the selected
protein targets; therefore, they were deemed viable candidates for further in vitro and in vivo evaluation.Communicated by Ramaswamy H. Sarma.