Contribution of the lycotetraose moiety of α-tomatine to the interaction with the main proteases of coronaviruses PEDV and SARS-CoV-2

We have investigated the interaction of the steroidal alkaloid tomatidine (TD) and its glycosylated derivative -tomatine (αTM) with the 3C-like protease (3CLpro) of PEDV and with the main protease (Mpro) from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible forWe have investigated the interaction of the steroidal alkaloid tomatidine (TD) and its glycosylated derivative α-tomatine (αTM) with the 3C-like protease (3CLpro) of PEDV and with the main protease (Mpro) from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19, using molecular modeling. αTM can generate more stable complexes with both proteases than TD. The lycotetraosyl moiety of αTM largely occupies the binding cavity, pushing the steroid moiety outside of the groove, whereas with the aglycone TD fits into the site. The specific contribution of the tetrasaccharide was further investigated via the modeling of the unsubstituted lycotetraose molecule, and the glycoalkaloid demissine (DEM) bearing a lycotetraose unit and a different steroidal skeleton demissidine. The binding of DEM to the proteases is essentially driven by the carbohydrate moiety, projecting the aglycone outside of the binding cavity. This study shed light on the protein-binding capacity of the lycotetraose unit. COVID-19, using molecular modeling. TM can generate more stable complexes with both proteases than TD. The lycotetraosyl moiety of TM largely occupies the binding cavity, pushing the steroid moiety outside of the groove, whereas with the aglycone TD fits into the site. The specific contribution of the tetrasaccharide was further investigated via the modeling of the unsubstituted lycotetraose molecule, and the glycoalkaloid demissine (DEM) bearing a lycotetraose unit and a different steroidal skeleton demissidine. The binding of DEM to the proteases is essentially driven by the carbohydrate moiety, projecting the aglycone outside of the binding cavity.