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Abstract
Computer-Aided Drug Design (CADD) plays a crucial role in accelerating the drug discovery process by identifying drug candidates, improving the efficacy of lead compounds, and elucidating the structureactivity relationships between drugs and target proteins. As CADD continues to revolutionize drug discovery, we can investigate the potential of utilizing diverse bioactive compounds, including polyphenols, as medicinal agents. However, the functioning mechanism of these bioactive compounds remains unknown. Herein, we first used CADD approaches to investigate the biological effects of the resveratrol which belongs to stilbenoids group of polyphenols. By using molecular docking and molecular dynamics (MD) simulations, we found that resveratrol and its analogs exert their inhibitory effects by competing with the substrate dNTPs in nucleotide-dependent enzymes and then blocking elongation of chain polymerization. Building upon this understanding of resveratrol’s inhibitory mechanism, we extended our investigation to explore additional polyphenols. During the COVID-19 pandemic, a dataset of polyphenols was virtually screened against SARS-CoV-2 main protease (Mpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp). Our findings identified several polyphenols, such as Petunidin 3-O-(6”-p-coumaroyl-glucoside) exhibiting promising binding affinities against these targets. To further develop potential drugs against COVID-19, we also virtually screened 728 approved drugs and 26,193 compounds for COVID-19 drug discovery. The lead compounds obtained from these studies show convincing binding affinities, which pave the way for future drug design.