In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

Docking analysis of propolis's natural compound was successfully performed against SARS-CoV-2 main protease (Mpro) and spike protein subunit 2 (S2). Initially, the propolis's protein was screened using chromatography analysis and successfully identified 22 compounds in the propolis. Four compounds were further investigated, i.e., neoblavaisoflavone, methylophiopogonone A, 3′-Methoxydaidzin, and genistin. The binding affinity of 3′-Methoxydaidzin was −7.7 kcal/mol, which is similar to nelfinavir (control), while the others were −7.6 kcal/mol. However, we found the key residue of Glu A:166 in the methylophiopogonone A and genistin, even though the predicted binding energy slightly higher than nelfinavir. In contrast, the predicted binding affinity of neoblavaisoflavone, methylophiopogonone A, 3′-Methoxydaidzin, and genistin against S2 were −8.1, −8.2, −8.3, and −8.3 kcal/mol, respectively, which is far below of the control (pravastatin, −7.3 kcal/mol). Instead of conventional hydrogen bonding, the π bonding influenced the binding affinity against S2. The results reveal that this is the first report about methylophiopogonone A, 3′-Methoxydaidzin, and genistin as candidates for anti-viral agents. Those compounds can then be further explored and used as a parent backbone molecule to develop a new supplementation for preventing SARS-CoV-2 infections during COVID-19 outbreaks.