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AbstractThe COVID-19 pandemic has caused adverse health (severe respiratory, enteric and systemic infections) and environmental impacts that have threatened public health and the economy worldwide. Drug repurposing and small molecule multi-target directed herbal medicine therapeutic approaches are the most appropriate exploration strategies for SARS-CoV-2 drug discovery. This study identified potential multi-target-directed Parkiabioactive entities against SARS-CoV-2 receptors (S-protein, ACE2, TMPRSS2, RBD/ACE2, RdRp, MPro, and PLPro) using ADMET, drug-likeness, molecular docking (AutoDock, FireDock and HDOCK), molecular dynamics simulation and MM-PBSA tools. One thousand Parkiabioactive entities were screened out by virtual screening and forty-five bioactive phytomolecules were selected based on favorable binding affinity and acceptable pharmacokinetic and pharmacodynamics properties. The binding affinity values of Parkiaphyto-ligands (AutoDock: −6.00–−10.40 kcal/mol; FireDock: −31.00–−62.02 kcal/mol; and HDOCK: −150.0–−294.93 kcal/mol) were observed to be higher than the reference antiviral drugs (AutoDock: −5.90–−9.10 kcal/mol; FireDock: −35.64–−59.35 kcal/mol; and HDOCK: −132.82–−211.87 kcal/mol), suggesting a potent modulatory action of Parkiabioactive entities against the SARS-CoV-2. Didymin, rutin, epigallocatechin gallate, epicatechin-3-0-gallate, hyperin, ursolic acid, lupeol, stigmasta-5,24(28)-diene-3-ol, ellagic acid, apigenin, stigmasterol, and campesterol strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging and spread. Furthermore, ACE2, TMPRSS2, and MPro receptors possess significant molecular dynamic properties, including stability, compactness, flexibility and total binding energy. Residues GLU-589, and LEU-95 of ACE2, GLN-350, HIS-186, and ASP-257 of TMPRSS2, and GLU-14, MET-49, and GLN-189 of MPro receptors contributed to the formation of hydrogen bonds and binding interactions, playing vital roles in inhibiting the activity of the receptors. Promising results were achieved by developing multi-targeted antiviral Parkiabioactive entities as lead and prospective candidates under a small molecule strategy against SARS-CoV-2 pathogenesis. The antiviral activity of Parkiabioactive entities needs to be further validated by pre-clinical and clinical trials.