The outbreak of coronavirus in 2019-2020 is caused by Severe Acute Respiratory Syndrome Corona Virus (SARS-COV-2) [1] [2] [3] [4] . It is a positive-sense single-stranded RNA virus that caused a total of 75,465 reported cases up to February 2020 in China [5] [6] . Increased risk of world wide spread comprises serious life-threatening issues against human safety. Fever, cough, and shortness of breath are the main symptoms of the disease that may leads eventually to pneumonia with a mortality rate of 1-3% [7] [8] [9] [10] [11] .
Currently, there are no approved drugs for coronavirus infectious. Even though antiviral drugs such as inhibitors against protease, integrase and or polymerase enzymes designed and are in advance studies [12] [13] . Among these inhibitors, anti-protease inhibitors seem to act effectively in blocking virus replication and provide a promising treatment for SARS and MERS diseases.
Given the protease vital role in the virus life cycle and its maturation via functional protein production from their precursor, it seems to be a good target for drug design in viral infections as COVID-19 infection as well.
Based on data available in the PUBMED database (https://www.ncbi.nlm.nih.gov/pubmed/) COVID-19 protease, EC 3.4.2 is a protein with 305 residues contrast to SARS protease with 306 amino acid residues. Sequence alignment using EMBOSS Stretcher server (www.ebi.ac.uk) reviled that corona protease compared to SARS protease contains one amino acid deletion at position 144 (Cys) as well as about 10 mutations along it sequence stretch as depicted in scheme 1. These changes in COVID-19 protease sequence may lead to the different global architecture of protein and especially in its binding or catalytic site, in such a way the localization of binding sites in COVID-19 shifted to neighbors' residues contrast to that's of SARS protease.
Binding site survey for these two proteases using Computed Atlas of Surface Topography of proteins (http://sts.bioe.uic.edu/castp/) server confirmed these changes in enzyme binding site. Table 1 represents the binding site residues for SARS and COVID-19 protease. As it is evident there is only three residues similarity between two enzymes at positions 140-142 different amino acid constituent and geometry expectedly need different inhibitors with different stereochemistry. Based on this fact it is necessary to search for different inhibitors for coronavirus, the investigation that is the main topic of this study. In the next step, we carried out active site-directed docking of the selected ligands in ArgusLab software to study the binding capacity of ligands to fit the active site. The binding energies obtained from our docking our blind and active site-directed experiments are shown in table 2. Pearson's two-tailed test of correlation was performed between blind and active site-directed docking reveals that there is no significant correlation between blind and site-directed energies (p-value >.05) and this means that the mechanisms underlie the interactions between ligand and protease is not the same and these two energies are completely independent variables and could be sums for comparative purpose. Figure 3 shows the total binding energies for ligands during our experiments. Based on our findings and as it is clear Tipranavir seems to be the most potent inhibitor for COVID-19 protease. Clinical trials reveal that Tipranavir is capable of viruses' replication in patients resistant to other protease inhibitors and resistance against this drug needs multiple mutations to take place simultaneously in protease genes [22] .
The application of the drug in combination with one of the antiretroviral drugs as Ritonavir is approved for HIV-1 treatment by the FDA [23] . The second effective drug we introduced is Cefditoren, a cephalosporin antibiotic with broad-spectrum, administered for different conditions as pneumonia, acute bacterial and chronic bronchitis [24] [25] . Indinavir is the third effective inhibitor we candidate for COVID-19 treatment. Considering the miscellaneous drugs available for HIV-1 treatment it is not currently recommended for HIV-1 treatment due to its side effects [26] . However, it is shown that Indinavir by decreasing viral replication increases the life expectancy of the patient for several years in viral infections [27] . The low water solubility of Indinavir requires plenty of water to dink to prevent its precipitation and crystallization as in kidneys [28] .
Atazanavir is the forth protease inhibitor that we recommend for COVID-19 infections. This inhibitor structural mimic the transition state of proteolysis at the Phe-Pro cleavage site. Atazanavir is prescribed for HIV-1 treatment in conjunction with an antiretroviral drug [29] . Given that human proteases could not hydrolyze the Phe-Pro bonds so Atazanavir does not inhibit human proteases at all [30] [31] . [39] [40] . The eighth drug we recommend for the clinical trial is Ritonavir which is a known inhibitor for HIV-1 protease. This inhibitor does not or rarely used alone for HIV-1 infectious and instead it is most often used in conjunction with other protease inhibitors to boost their antiviral action. Ritonavir itself inhibits liver and intestine enzymes that metabolize protease inhibitors and by the way, allows lower doses for these drugs to exert their effects [41] [42] [43] [44] . The ninth drug seems useful for the clinical trial is Erythromycin the well known and safe antibiotic for respiratory tract infections and finally, Amprenavir is the tenth drug we recommend for a clinical trial for COVID-19
infections that have no vaccine and no approved drug with a reasonable rate of incidence and increasing percent of mortality [45] [46] . 
Our results indicate that there are structural differences between primary structures of proteases for COVID-19 contrasts to that's of SARS which leads to altered enzyme binding sites. We hypothesize that these alterations cause the enzyme, not to respond to anti-SARS protease inhibitors for treatment [47] [48] .
During this work and via re-examining HIV-1 protease inhibitors and different anti bronchitis antibiotics we tried to find more effective inhibitors for COVID-19 treatment. Finally, we picked up the following order for inhibitory potency among anti-HIV-1 protease inhibitors:
Tipranavir>Indinavir>Atazanavir>Darunavir>Ritonavir>Amprenavir Similarly, the following order for anti bronchitis was obtained
Considering this fact that all the drugs used in this study are approved by FDA for clinical application we hope that our findings considered for clinical trials in COVID-19 patients to overcome the world wide current outbreak of coronavirus.