The spike (S) protein of SARS-CoV-2 harbors the receptor-binding domain (RBD) that mediates the virus's entry to host cells. The aim of this study was to identify novel inhibitors that target the RBD domain of S-protein through computational screening of chemical and natural compounds. Method: The S protein was modelled from the recently resolved and the previously described SARS-CoV protein structures. CLC Drug Discovery was used to computationally screen for potential inhibitory effects of

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... rently prescribed drugs (n= 22) anti-viral natural drugs (n=100), natural compounds (n= 35032). QSAR was also performed. Results: Among currently precribed drugs to treat SARS-CoV2, hydroxychloroquine and favipiravir were identified as the best binders with an average of 4Hbonds, the binding affinity (BA): -36.66 kcal·mol−1, and interaction energy (IE): -6.63 kcal·mol−1. After the evaluation of anti-viral compounds, fosamprenavir and abacavir showed effective binding of 5H-bonds, with average BA: -18.75 kcal·mol−1, and IE: -3.57 kcal·mol−1. Furthermore, screening of 100 natural anti-viral compounds predicted potential binding modes of glycyrrhizin, nepritin, punicalagin, EGCG, and theaflavin (average BA: -49.88 kcal·mol−1, and IE: -4.35 kcal·mol−1). Additionally, the study reports 25 natural compounds that showed effective binding with an improved average BA: 51.46 kcal·mol−1. Conclusion: Using computational screening, we identified potential SARSCoV-2 spike inhibitors that bind to the RBD region.