Chemical constituents from coconut waste and their in silico evaluation as potential antiviral agents against SARS-CoV-2

Eleven compounds were isolated from the ethyl acetate extract of Cocos nucifera L endocarp, jezonofol 1, scirpusin A 2, cassigarol G 3, maackin A 4, threoguiacyl glycerol-8’-vanillic acid ether 5, erythroguiacyl glycerol-8’-vanillic acid ether 6, apigenin-7-O-β-D-glucoside 7, piceatannol 8, p-hydroxy-benzoic acid 9, protocatechuic acid 10 and vanillic acid 11. Compounds 1-7 were isolated for the first time from the plant. The isolated compounds were virtually screened against four critical components of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the main protease (M(pro)), papain-like protease (PL(pro)), nonstructural protein 13 (nsp13) and RNA dependent RNA polymerase (RdRp). Stilbene dimers 1-4 showed remarkable binding affinities towards the investigated targets (binding energy <−7.6 kcal/mol). Compounds 1, 3 and 4 interacted with the catalytic dyad (Cys145-His41) at the active pocket of M(pro) which is essential for achieving good inhibitory activity. Compounds 1-3 showed molecular interaction with the conserved ubiquitin-specific protease residues of PL(pro), responsible for binding ability at different active sites of nsp13, which are crucial for decreasing the resistance caused by viral immune evasion. Compounds 2 and 3 showed the ability to bind at different active sites of nsp13, which is a key binding site for reducing antiviral resistance. Finally, compounds 1-3 showed the ability to bind with RdRp before and after RNA binding. Our findings suggested that the dimeric stilbene skeleton is a promising candidate for developing anti-COVID-19 drugs. Particularly, 1, 2 and 3, showed a promiscuity pattern binding to multiple targets of SARS-CoV-2 replication. Herein, 20 ns molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations were performed to estimate the binding affinity of the most potent three compounds against the viral SARS-CoV-2 targets. MM-GBSA calculations unveiled the outshine potency of compound 1 towards PL(pro) with a binding energy of −60.7 kcal/mol. Structural and energetic analyses over 20 ns MD simulation displayed the high stability of compound 1 in complex with PL(pro). The list of the compounds was considered herein forms a primer for clinical investigation in COVID-19 patients and directing for further antiviral examinations. Drug likeness properties of compounds 1-4 were evaluated.