3CL-Pro (or M-Pro) is the SARS-CoV-2 main protease,  responsible for the cleavage of the large polyprotein 1ab transcript and the liberation of eleven proteins , responsible for viral growth and replication. It acts exclusively as a homodimer, while monomers are inactive. Due to its pivotal role, 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and the subject of a number of therapeutic interventions, targeting its catalytic domain. A number of potential drug candidates have been reported, including some natural products. Here, we have investigated in silico, through fully flexible binding and extensive molecular dynamics simulations, the natural product space for the identification of potential candidates of 3CL-Pro dimerization inhibitors. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, isolated from the fruits of Citrus japonica var. margarita (kumquat), is a potent inhibitor of 3CL-Pro dimerization. A search of the ZINC natural products database identified another 16 related molecules, which possess interesting pharmacological properties. We propose that fortunellin and its  analogs might be the basis of novel pharmaceuticals  against SARS-CoV-2 induced COVID-19 disease.
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.
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