  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.
