Inhibition of SARS-CoV-2 main protease by phenolic compounds fromManilkara hexandra(Roxb.) Dubard assisted by metabolite profiling andin silicovirtual screening

SARS-CoV-2 is a novel coronavirus that was first identified during the outbreak in Wuhan, China in 2019. It is an acute respiratory illness that can transfer among human beings. Natural products can provide a rich resource for novel antiviral drugs. They can interfere with viral proteins such as viral proteases, polymerases, and entry proteins. Several naturally occurring flavonoids were reported to have antiviral activity against different types of RNA and DNA viruses. A methanolic extract ofManilkara hexandra(Roxb.) Dubard leaves is rich in phenolic compounds, mainly flavonoids. Metabolic profiling of the secondary metabolites ofManilkara hexandra(Roxb.) Dubard leaves methanolic extract (MLME), and bark ethyl acetate (MBEE) extract using LC-HRESIMS resulted in the isolation of18compounds belonging to a variety of constituents, among which phenolic compounds, flavones, flavonol glycosides and triterpenes were predominant. Besides, four compounds (I-IV) were isolated and identified as myricetinI, myricitrinII, mearnsitrinIII, and mearnsetin-3-O-beta-d-rutinosideIV(compoundIVis isolated for the first time from genusManilkara) and dereplicated in a metabolomic study as compounds3,5,6, and12, respectively. The molecular docking study showed that rutin, myricitrin, mearnsitrin, and quercetin 3-O-beta-d-glucoside have strong interaction with SARS-CoV-2 protease with high binding energy of -8.2072, -7.1973, -7.5855, and -7.6750, respectively. Interestingly, the results proved that rutin which is a citrus flavonoid glycoside exhibits the strongest inhibition effect to the SARS-CoV-2 protease enzyme. Consequently, it can contribute to developing an effective antiviral drug lead against the SARS-CoV-2 pandemic.