A few drugs have been used for treating Coronavirus Disease 2019 (COVID-19) patients such as Remdesivir (RDS) and Favipiravir (FPV) which are considered as nucleotide and nucleoside, respectively, inhibitors that interfere with the assembly of the viral RNA. RDS is used for the treatment of Ebola 1 and Marburg viruses 2 and SARS and MERS infections 3 . In a compassionate-clinical use of RDS in hospitalized COVID-19 patients breathing ambient air or on oxygen support, clinical improvement was seen in 36 of 53 patients (68%) 4 which is still a humble recovery especially in the case of more severe and critical patients. Like RDS, FPV (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a nucleoside analogue used as an antiviral drug that halts the replication of the viral RNA due to its incorporation in the newly-made RNA strand of widerange viruses 5 . FPV was recorded to induce inhibition to seasonal and avian influenza viruses even those strains that are resistant to neuraminidase inhibitors as approved using cell culture and experimental animals 6 .
Due to the availability of the RdRP 3D structure 7 , docking methods in the present work were employed to enhance production of drugs that bind with high affinities to the binding sites of the enzyme. This might block the activity of the enzyme, halt the viral RNA building, and eventually stop the viral replication.
In the current study, drugs (Table 1) were employed to target active binding sites of the SARS-CoV-2 RdRP (PDB ID: 6m71; https://www.rcsb.org/), after removing cofactors from the structure using PyMOL 8 . MMs, members of the macrocyclic lactone family, were selected according to a report that IMT, a member of the same family, was effective in minimizing the replication of the COVID-19 in cell culture 9 . For BM, the selection was according to its inhibition effects on the polymerase-based initiation of mRNA of the influenza virus 10 . In the case of TF selection, it was previously 
The outcomes of the present investigation shown in table 2 unveiled the highest affinity values for MMA-35O, MMA3, MMA45O, and IMT when binding to RdRp followed by BM and TF. The chemical structures of these ligands are displayed in figure 1 .
The results showed that the palm subdomain in motif B of the RdRP is engaged by the MMA35O (Figure  2A ). The bonds of the attachment between the ligand and the protein are shown in figures 3-5A. MMA3 revealed its binding to the bindings sites in the RNA template tunnel groove of the F motif of the RdRP enzyme ( Figure 2B ). The linkages between the ligand and the enzyme are displayed in figures 3-5B. Moreover, MMA45O displayed attachment to the binding sites located in the B and F motifs in the way of RNA template entry ( Figure 2C ). The ligand-protein based bonds are shown in figures 3-5C. IMT revealed binding to the binding sites present in the C and F motifs in the inlets of RNA template and NTPs and the outlet of the product hybrid ( Figure 2D ). For the linkages, the ligand-enzyme connection is shown in figures 3-5D. For the BM, the binding site location was in the B and F motifs of the inlets of RNA template and NTPs and 
The active sites of the RdRP, also known as nsp12, are located in the motifs A to G 7 . This activity is probably due to different directions taken by the major components; RNA template, NTPs, and product hybrid, involved in the building of the new viral RNA strands. The finding of the present study revealed that the palm subdomain in the motif B of the RdRP is bound by the MMA35O. The palm subdomain (Residues T582-P620 and T680-Q815) is an important part of the core region of the RdRP that participates in the stability of the enzyme structure along with fingers subdomain (Residues L366-A581 and K621-G679) and a thumb subdomain (Residues H816-E920) 7 . Hypothetically, the presence of the MMA35O in the bound region may increase the chances of halting the enzyme activity especially when this region is considered adjacent to the passage of the RNA building materials. MMA3 showed its binding to the F motif of the RdRP enzyme. The F motif is a critical part through which the RNA template is expected to enter to the active sites in the motifs A and C to engage in the process of the RNA replication. This attachment region is located in the active groove that is used as an RNA template entry passage. Typically, this means that the occurrence of the ligand in this pocket might enhance the chance of disrupting the replication of the viral RNA strand.
Another molecule that expressed binding to RdRP is MMA45O. The drug attached to the binding sites in the motifs B and F. The bound ligand was seen sitting in the groove, RNA template passage entry to the motif A and C, clamped by the F motif. Such occasion might interfere with the activity of the RdRP, thereby stopping its activity and eventually finishing the cycle of viral replication. Motif A (Residues 611-TPHLMGW-DYPKCDRAM-626) has a conserved divalent-cationbinding residue (D618) which is similar to that in other viral RdRP such as in HCV (D220) and poliovirus (D233). IMT revealed binding to motif C and F. Motif C consists of residues of 753-FSMMILSDDAVVCFN-767 including the catalytic residues of 759-SDD-761 7 .
In the present study, Baloxavir marboxil displayed successful binding to the active sites in the B and F motifs of the RdRP. Baloxavir marboxil suppresses the activity of the viral replication of the influenza virus by inhibiting the polymerase PA subunit 13 . Since the target of this drug is the viral polymerase, this might be a great drug of choice for treating COVID-19 patients. The TF showed strong binding activity to the polymer- ase of the virus. Tadalafil is an inhibitor to the phosphodiesterase type 5 component utilized to manage erectile dysfunction 14 . This could be applied as a great drug of choice for treating COVID-19 cases especially when this drug is used to treat pulmonary arterial hypertension 15 .
The current work provided a group of drugs that could be further studied in vitro, in vivo, and in clinical trials to find whether they are effective against the SARS-CoV-2 (COVID-19) virus and thereby, quickly helping to manage the pandemic around the world.