The natural polyphenol fortunellin and its structural analogs are inhibitors of the SARS-CoV-2 main proteinase dimerization, as revealed by molecular simulation studies.

3CL-Pro (or M-Pro) is the SARS-CoV-2 main protease, acting as a homodimer, is responsible for the cleavage of the large polyprotein 1ab transcript in proteins acting on viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and the subject of therapeutic interventions, targeting its catalytic domain. A number of drug candidates have been reported, including some natural products. Here, we investigated in silico, through binding and molecular dynamics simulations, the natural product space for the identification of candidates of 3CL-Pro dimerization inhibitors. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, is a potent inhibitor of 3CL-Pro dimerization. A search of the ZINC natural products database identified another 16 related molecules, including apilin and rhoifolin, with interesting pharmacological properties. We propose that fortunellin and its structural analogs might be the basis of novel pharmaceuticals and dietary supplements against SARS-CoV-2 induced COVID-19 disease.