Potential therapeutic intervention of melatonin against COVID-19: A comparative pharmacokinetic study

Melatonin synthesis is primarily regulated by environmental light-dark cycle and is well known for its biological rhythm regulation and its potent antioxidant and anti-inflammatory properties across species. The present investigation focuses on the potential actions of melatonin as a therapeutic agent against COVID-19 and these actions are compared with other commonly used pharmacological agents of this kind including methylprednisolone, doxycycline, oseltamivir, and remdesivir. The comprehensive comparisons of pharmacokinetic profiles include their absorption, distribution, metabolism, and excretion (ADME) properties. The further in-depth analyses on their target identification, functional enrichment are performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, construction of protein-protein interaction (PPI) networks, and molecular docking. These analyses elucidate the potential correlation of melatonin with critical hub targets implicated in COVID-19 pathogenesis. The results from pharmacokinetics indicates that melatonin has the higher bioavailability than the other tested drugs due to its low molecular weight, lipophilicity, lack of P-glycoprotein (P-gp) along with inhibitory action on cytochrome P450 1A2 (CYP1A2). GO and enriched KEGG analyses suggests that melatonin-mediated modulation of COVID-19 pathogenesis likely targets the AGE-RAGE pathway, HIF-1α signaling, and apoptosis. Furthermore, PPI network analysis also shows that melatonin has the highest nodes and edges, as well as the greatest average node degree score and highest common potential targets with the genes associated with the development of COVID-19. Notably, molecular docking study demonstrates the substantial interactions of melatonin with principal hub targets TP53, AKT1, IL6, TNF, IL1B, BCL2, EGFR, STAT3, CASP3, and NFKB1. Hence, melatonin has several significant pharmacokinetic advantages compared to selected therapeutic agents which may appear to modulate multiple facets of COVID-19 pathology. Based on the significant pharmacokinetic advantages of melatonin over the commonly used other drugs, the substantial clinical studies are necessary to establish its methods of application as a potential therapeutic against SARS-CoV-2 in the near future.