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Acharya Balkrishna,1,2 Subarna Pokhrel,1 Hoshiyar Singh,1 Monali Joshi,1 Vallabh Prakash Mulay,1 Swati Haldar,1 Anurag Varshney1,2 1Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India; 2Department of Allied and Applied Sciences, University of Patanjali, Haridwar, 249405, Uttarakhand, IndiaCorrespondence: Anurag Varshney; Swati HaldarDrug Discovery and Development Division, Patanjali Research Institute, Roorkee-Haridwar Road, Haridwar, 249405, Uttarakhand, IndiaTel +91-1334-244107, Ext. 7458; +91-1334-244107, Ext. 7481Fax +91-1334-244805Email anurag@prft.co.in; swati.haldar@prft.inPurpose: SARS-CoV-2 engages human ACE2 through its spike (S) protein receptor binding domain (RBD) to enter the host cell. Recent computational studies have reported that withanone and withaferin A, phytochemicals found in Withania somnifera, target viral main protease (MPro) and host transmembrane TMPRSS2, and glucose related protein 78 (GRP78), respectively, implicating their potential as viral entry inhibitors. Absence of specific treatment against SARS-CoV-2 infection has encouraged exploration of phytochemicals as potential antivirals.Aim: This study aimed at in silico exploration, along with in vitro and in vivo validation of antiviral efficacy of the phytochemical withanone.Methods: Through molecular docking, molecular dynamic (MD) simulation and electrostatic energy calculation the plausible biochemical interactions between withanone and the ACE2-RBD complex were investigated. These in silico observations were biochemically validated by ELISA-based assays. Withanone-enriched extract from W. somnifera was tested for its ability to ameliorate clinically relevant pathological features, modelled in humanized zebrafish through SARS-CoV-2 recombinant spike (S) protein induction.Results: Withanone bound efficiently at the interacting interface of the ACE2-RBD complex and destabilized it energetically. The electrostatic component of bi