Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening.

Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).

An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

Polyphenols as alternative treatments of COVID-19.

Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6″-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.