Psoralidin acts as a dual protease inhibitor against PLpro and Mpro of SARS-CoV-2

Abstract

The emergence of new coronavirus variants and concerns about vaccine effectiveness against these novel variants emphasize the need for broad-spectrum therapeutics targeting conserved coronaviral non-structural proteins. Accordingly, a virtual library of 178 putative inhibitors targeting SARS-CoV-2 Papain-like protease (PL^pro) was compiled through a systematic review of published literature and subsequently screened using molecular docking. Selected hits were analyzed for protease inhibitory activities, binding strength, and antiviral activities against HCoV229E-based surrogate system and subsequently against SARS-CoV-2 for validation. Differences in potential modes of action were investigated using an HCoV229E-based system, combined with in silico and biophysical methods against SARS-CoV-2 system. Of the 178 hits, 13 molecules showed superior docking scores against PL^pro and met the inclusion criteria for further investigations. Of these, seven showed notable inhibitory activities against PL^pro. Particularly, both Psoralidin and Corylifol-A exhibited superior and, importantly, dual activities against SARS-CoV-2 M^pro. Both molecules were found to be biologically active against HCoV229E and SARS-CoV-2; however, Psoralidin exhibited more consistent effects and was relatively well-tolerated. Detailed in silico analyses of their interactions with the two proteases identified differences in their modes of action, primarily due to differences in their binding of PL^pro. Based on these findings, we propose Psoralidin as a potential candidate for further development as a broad-spectrum antiviral and Corylifol-A as an ideal candidate for lead optimization.