The natural polyphenol fortunellin is a dimerization inhibitor of the SARS-CoV-2 3C-like proteinase, revealed by molecular simulations

Panagiotopoulos, Athanasios A.; Kotzampasi, Danai-Maria; Sourvinos, George; Kampa, Marilena; Pirintsos, Stergios; Castanas, Elias; Daskalakis, Vangelis

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.