Although many viral infections are self-limiting, other are real health challenges like COVID-19 since many viruses possess just few drug gable targets to be treated with small drug molecules. Corona virus genome encodes for up to 17 main proteins. Orf1ab encodes for polyprotein. COVID-19 structural proteins are the spike S, membrane M, envelope E and the nucleocapsid N protein while other are non-structural proteins designated as NSP1-13 for non-structural proteins. Among NSP the most important corona virus targets for developing antiviral drugs are the papain-like protease, PDB ID: 6m03 and RNA polymerase NSP12, PDB ID: 6nur. NCBI, NIH Genbank, Uniprot, PDB, DrugBank, ChemSpider databases and bioinformatics editor softwares like ICM Mol soft pro and Swiss Dock were used in addition to the in vitro lab model of viral protease were integrated to retrieve and analyze corona virus targets and to select the candidate ligands in an attempt to evaluate the inhibitory efficacy of different experimental and approved drugs which were further optimized and searched for the highly similar approved drug. This step aims to adopt drug repurposing to speed the development of antiviral drugs and recommend rational in vivo and clinical studies. After COVID-19 targets had been analyzed the drugs that shared > 70% similarity to the binding sites of those targets were reversin, pentagastrin, remdesivir, norfloxacin and nitazoxanide against COVID-19 papain-like protease whereas benzyl glutathione, lopinavir and hydroxymethylglutathione against RNA polymerase. The anti-resistance reversin showed the highest inhibitory efficacy against COVID-19 papain-like protease as indicated by the ligand-protease binding energy with Mol soft pro analysis. The calculated inhibitory binding was -137.30 kJ/mol z > 1.9 as compared with the tetrazapentadecanoate -129.57 kJ/mol z = 4.0, whereas remdesivir, pentagastrin, nitazoxanide and norfloxacin had a moderate antiprotease activity (>- 100 kJ/mol). Norfloxacin shoresults showed a slight consistency between in vitro and in silico models. Although benzyl glutathione is an experimental compound, however it had the highest RNA polymerase inhibiting efficacy with -129 kJ/mol binding energy which is even higher than lopinavir and Favinavir. From the overall results, reversin, oligopeptides, quinolones and antiviral drugs may widen the treatment options for COVID-19 if further evaluated in clinical studies