Molecular docking and pharmacokinetic studies of naturally occurring flavonoid glycosides and their activity against COVID-19 viral proteins

Abstract

Covid-19 is an illness that is caused by a virus named Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2). These viruses belong to the subfamily Orthocoronavirinae within the family Coronaviridae. Covid 19 disease causes serious respiratory illness similar to pneumonia and lung failure. The World Health Organization (WHO), the arm of the United Nations dedicated to public health, announced that the novel coronavirus outbreak was a worldwide pandemic in March 2020. [1] Natural products have the potential to serve as an important source to treat Covid 19 since a lot of these products have been used to treat other viral diseases like the HIV, MERS-CoV and influenza. [2] These products, for instance the flavonoids, alkaloids and peptides possess antiviral properties., Essential oils and extracts that originate from plants are an important source of bioactive metabolites. These sources are extensively used in the pharmaceutical industry to treat inflammation, cancer, oxidative processes and viral infections. [3] In this comprehensive paper we focus on the ability of these naturally occurring substances as a potential therapeutic agent against Covid 19 disease. Through computational analysis it can be observed that flavonoids as a group of compounds compose effective viral enzyme inhibitors and possess antiviral properties. Hence these compounds are a feasible target for antiviral drugs against the action of SARS-CoV-2 due to their useful therapeutic properties. The action of ten flavonoid glycosides, namely Rutin, Nicotiflorin, Naringin, Diosmin, Apigetrin, Spiraeoside, Kaempferol, Quercetin, Isoquercetin and Astragalin against four viral proteins of SARS-CoV-2, namely Spike protein, RNA-dependent-RNA polymerase (RdRp), 3-chymotrypsin like protease (Main protease, Mpro) and Papain-like protease (PLpro) was analysed using molecular docking and pharmacokinetic studies. Although sufficient in silico work has been done using general antioxidants against SARS-CoV-2, there has been a significant paucity in the amount of research carried out using the specific antioxidant subgroup naturally occurring flavonoid glycosides against SARS-CoV-2. This project has been undertaken with the intention of filling this gap in the literature. The Protein Data Bank files of the ligands and viral proteins were obtained from PubChem and RCSB PDB website, followed by energy minimization and geometry optimization. Molecular docking with the chosen ligands versus the viral proteins was done and the results were visualized and binding interaction analysis was done. Pharmacokinetic analysis of ligands to determine drug likeness was done and the results were tabulated and analysed. Upon analysis of the docking results, it was found that all residues found in the docking result for each ligand bound to the active site residues of the viral proteins. This suggests that the natural compounds chosen have potential inhibitory activity against the viral proteins. The ligands with the lowest binding energy for each viral protein were Naringin and Diosmin (-8.3 kcal/mol) for RNA-dependent-RNA polymerase (RdRp), Apigetrin (-7.5 kcal/mol) for Main protease (Mpro), Diosmin (-7.2kcal/mol) for Spike protein and Naringin (-8.4 kcal/mol) for Papain-like protease (PLpro). The in silico analysis of these compounds against the multiple viral proteins has provided information about which type of flavonoid glycoside has optimum binding efficiency and this can be incorporated into further in vivo and in vitro studies about the action of flavonoid glycosides against COVID-19 disease progression. Following validation by further studies, these compounds can be formulated into standalone or combinatorial drugs that can be incorporated into the COVID-19 treatment regimen. These compounds can be scaled up to be manufactured on an industrial level and can be distributed as therapeutic/nutritional supplements in the form of pills or powder.

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