Objective:To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell lines.Methods:First,compounds were retrieved from the PubChem database and predicted for their druggabil-ity using the MolSoft web server,and compounds having drug-like property were predicted for major adverse drug reactions like cardiotoxicity,hepatotoxicity,arrhythmia,myocardial infarction,and nephro-toxicity using ADVERpred.Docking of nontoxic antiviral compounds with spike glycoprotein and main protease 3CLpro was performed using AutoDock vina by PyRx 0.8 version.The stability of compound-protein interactions was checked by molecular dynamic(MD)simulation using Schrodinger Desmond software.Results:Based on the druggable and nontoxic profile,nine compounds were selected.Among them,Withanone from Withania somnifera showed the highest binding affinity and best fit at active sites 1 of spike glycoprotein(glycosylation site)and main protease 3CLpro via interacting with active site amino acid residues before and after MD simulation at 50 ns.Withanone,which may reduce the glycosylation of SARS-CoV-2 via interacting with Asn343 and inhibit viral replication.Conclusion:The current study reports Withanone as a non-toxic antiviral against SARS-CoV-2 and serve as a potential lead hit for further experimental validation.