Computational investigation of Arbutus serratifolia Salisb molecules as new potential SARS-CoV-2 inhibitors

Abstract

Abstract The outbreak of the current pandemic and the evolution of virus resistance against standard drugs led to the emergency of new and potent antiviral agents. Owing to its crucial role in viral replication, the protease enzyme is taken into survey to be a promising target for antiviral drug therapy using computational methods. In order to bring this important class of natural products in the limelight of research for prospective application as chemotherapeutic agents, the anti-SARS-CoV-2 activity of some bioactive molecules obtained from Arbutus serratifolia Salisb which is an Algerian medicinal plant, was investigated using in-silico methods. The molecular docking was performed by AutoDock Vina and UCSF Chimera, as well as ADMET and drug-likeness properties of these molecules were calculated using preADMET web-based application and the Swiss ADME server respectively. The phytochemicals (from Pr(1) to Pr(12)) were tested for their pharmacokinetic properties and docked into the main protease binding site on (PDB ID: 6Y84) in order to find a promising antiviral ligand. All tested molecules induced binding affinities into the binding pocket of (PDB ID: 6Y84) with energy scores ranging from moderate to better (from −6.4 to −8.00 kcal/mol). It is worthy to note that both Pr(2): (1S,5R,6S,8S,9S)-6,8-Dihydroxy-8-methyl-1,5,6,7,8,9-hexahydrocyclopenta [c] pyran-1-yl-β-D-glucopyranoside and Pr(7): ((1S,5S,6S,9S)-1-(β-D-Glucopyranosyloxy)-14-oxo-1,5,6,9-tetrahydro-1H-2,15-dioxacyclopenta [cd] inden-8-yl) methyl acetate, were found to be the best inhibitors with binding affinities (−7.7 kcal/mol and −8.0 kcal/mol), respectively, by virtue of the fact that all these tested molecules exhibited good binding affinities compared with those of Ritonavir and Nirmatrelvir (−1.73 and −1.93 kcal/mol), respectively, which are used as standard antiviral drugs to prevent viral growth. The amino acids: His-163; Glu-166; Arg-188; Thr-190 and Gln-192 represent the key residues of the interaction of SARS-CoV-2 main protease with Pr(7). Furthermore, the results of pharmacodynamic and pharmacokinetic investigations revealed that Pr(6), Pr(8) and Pr(9) uphold the drug-likeness criteria and more particularly, these substances can be absorbed by the human intestine. In addition, all these molecules were shown to be neither hepatotoxic nor significantly noxious to human organism. These natural products are therefore promising inhibitor candidates of viral main protease. However, further in-vitro, in-vivo and even clinical assays are required to probe their functional mechanisms and then to assess their antiviral potency against COVID-19.