Diosgenin and oleanolic acid interact with the SARS-CoV-2 Envelope protein and modulate viroporin-related cellular phenotypes

• 539 plant compounds selected for this study through In Silico followed by molecular simulation. • Diosgenin and Oleanolic has been used for In Vitro study. • Diosgenin and Oleanolic acid to block viroporin of SARS-CoV-2. The SARS-CoV-2 envelope (E) protein forms a cation-selective viroporin that disrupts cellular homeostasis and contributes to pathogenesis. In this study, we screened 539 phytocompounds with reported antiviral or anti-inflammatory activities against the E protein using molecular docking and dynamics simulations. Diosgenin and Oleanolic acid emerged as the top candidates, exhibiting strong binding energies (–26.30 and –21.58 kcal/mol, respectively), greater than the reference blocker Rimantadine (–10.73 kcal/mol). Further, in vitro analysis of these compounds in SARS-CoV-2 E protein overexpression model found that Diosgenin and Oleanolic acid abate the alkalization of the ERGC, comparable to that of the known viroporin blocker Rimantadine. Treatment of Diosgenin and Oleanolic acid reduces the transcript level of inflammatory markers IL6, TNFα, CCL5, CCL3, CXCL1, CXCL10 and TLR9 in the Envelope protein transfected A549 cells by more than 2-fold. These molecules also subside the level of RIPK1, NFκB and TNFα significantly (p