Molecular Docking Studies on Synthetic Therapeutic Agents for COVID-19

: Coronavirus disease (COVID-19) is an infectious disease caused by coronavirus 2 (SARS-CoV-2) which was detected for the first time in Wuhan China in December 2019. The rapid spread of this highly contagious and pathogenic virus led to the declaration of the pandemic by the World Health Organization (WHO) on March 11, 2020. In these conditions, the discovery of new antiviral agents is extremely important. For the development of the anti-SARS-CoV-2 drugs, the fastest way is to find potential molecules from the marketed drugs by molecular docking studies.


Introduction
Coronavirus disease (COVID- 19) is an infectious disease caused by coronavirus 2 (SARS-CoV-2) which was detected for the first time in Wuhan China in December 2019 [1]. The rapid spread of this highly contagious and pathogenic virus led to the declaration of the pandemic by the World Health Organization (WHO) on 11 March 2020.
The scientific community around the world is concerned with finding an effective treatment for the new coronavirus. Short-term efforts are focused on developing vaccines or inhibitors that act as protection against infection with the new coronavirus [2].

Molecular Docking Studies
Molecular docking studies have been performed to identify and visualize the most likely interaction of the ligand with the protein receptor [14]. The docking score and hydrogen bonds formed with the amino acids from of the group interaction atoms are used to predict the binding modes, the binding affinity, and the orientation of the docked ligands in the active site of the protein/enzyme receptor. The docking study have been carried out with synthetic anti-viral agents (13) [15][16][17][18] and anti-inflammatory agents (2) [5] (Figure 1), prepared using Spartan 14 Software [15].
In this study are five investigated SARS-CoV-2 targets: main protease (PD ID: 6W63, PD ID: 6WNP), spike glycoprotein (closed state) (PD ID: 6VXX), chimeric receptor-binding domain complexed with its receptor human ACE2 (PD ID: 6VW1), RNA-dependent RNA polymerase (PD ID: 6M71) and 3CL protease (3CL pro) (PD ID: 6M2N).  Docking studies were realized to obtain accurate predictions of the optimized conformations for both the ligands and protein target to form a stable complex. All compounds were docked on the crystal structure of SARS-CoV-2 main protease (PDB ID: 6W63). The docking pose of the co-crystallized X77 interacting with amino acid residues of the active site and the hydrogen bonds created with GLU 166 (2.721 Å) and GLY 143 (3.202 Å) are shown in Figure 2. The co-crystallized X77 (N-(4-tert-butylphenyl)-N- was taken as a reference ligand to compare the docking results of the studied compounds. The docking studies revealed that the docking scores of ten compounds are better than that of the co-crystallized X77 (docking score: −56.65; RMSD: 0.90 Å) (root mean square deviations) (Table 1, Figure 3 . In order to have a prediction as close to reality as possible, the RMSD value must be less than 2 Å [19]; for the compounds Ritonavir, Lopinavir, Darunavir and Boceprevir, it can be considered that the prediction is not very accurate.    After analyzing the docking study results, it was observed that all the studied ligands were placed in the same binding site (green sphere) of 6W63 as the co-crystallized X77, and it wasobserved they have the same orientation as the co-crystallized ligand ( Figure 4b).

SARS-CoV-2 Main Protease Receptor PD ID: 6WNP
Docking studies were realized to obtain accurate predictions of the optimized conformations for both the ligands and protein target to form a stable complex. All the compounds were docked on the crystal structure of the SARS-CoV   The docking study results reveals that all of the studied ligands were placed in the same binding site (green sphere) of 6WNP as the co-crystallized USG A 101, and it was observed that they have the same orientation as the co-crystallized ligand ( Figure 6); it was also observed that the correlation of the results obtained for two X-ray structures of SARS-CoV-2 main protease (6W63 and 6WNP) were downloaded from PDB bank (Protein data bank).

SARS-CoV-2 Spike Glycoprotein
All the compounds were docked on the crystal structure of SARS-CoV-2 spike glycoprotein (closed state) (PD ID: 6VXX).The docking pose of the co-crystallized NAG 1302 interacting with the amino acid residues of the active site and the hydrogen bonds created with ASN 122 (2.393 Å, 2.441 Å and 2.449 Å) are shown in Figure 7a. The cocrystallized NAG 1302 was taken as a reference ligand to compare the docking results of the studied compounds. The docking studies revealed that the docking scores of four compounds are smaller than that of the co-crystallized NAG 1302 (docking score: −18.42; RMSD: 0.51 Å) (Table 1, Figure 3  The docking study results reveal that all of the studied ligands were placed in the same binding site (green sphere) of 6VXX as the co-crystallized NAG 1302 but only Darunavir had the same orientation as the co-crystallized ligand (Figure 8).

SARS-CoV-2 Chimeric Receptor-Binding Domain Complexed with Its Receptor Human ACE2
All the compounds are docked on the crystal structure of SARS-CoV-2 chimeric receptor-binding domain complexed with its receptor human ACE2 (PD ID: 6VW1). The docking pose of the co-crystallized NAG 714 interacting with amino acid residues of the active site and the hydrogen bonds created with ASN 103 (2.434 Å, 2.310 Å and 2.562 Å) and GLN 81 (2.914 Å and 2.602 Å) are shown in Figure 9a. The co-crystallized NAG 714 was taken as a reference ligand to compare the docking results of the studied compounds. The docking studies revealed that only Favipavir (docking score: −32.12; RMSD: 0.01 Å) has a docking score smaller than that of the co-crystallized NAG 714 (docking score: −32.77; RMSD: 0.20 Å) (Table 1, Figure 3 The docking study results reveal that all of the studied ligands were placed in the same binding site (green sphere) of 6VW1 as the co-crystallized NAG 714, and it was observed they have the same orientation as the co-crystallized ligand ( Figure 10).

SARS-CoV-2 3CL Protease (3CL pro)
Docking studies were realized to obtain accurate predictions of the optimized conformations for both the ligands and protein target to form a stable complex. All compounds were docked on the crystal structure of SARS-CoV-2 3CL protease (3CL pro) (PD ID: 6M2N). The docking pose of the co-crystallized 3WL A interacting with the amino acid residues of the active site and the hydrogen bonds created with GLU 166 (3.016 Å), GLY 143 (3.104 Å and 2.969 Å) and ASN 142 (3.341 Å) are shown in Figure 12a. The cocrystallized 3WL A was taken as a reference ligand to compare the docking results of the studied compounds. All compounds except Oseltamivir, Ganciclovir, Aciclovir, Ribavirin and Favipavir have a docking score greater than co-crystallized 3WL A (docking score: −53.49; RMSD: 0.37 Å) (Table 1, Figure 3). Lopinavir has the best docking score: −83.22 (RMSD: 0.98 Å) and shows the occurrence of hydrogen bonds with the same amino acids GLU 166 (3.013 Å), GLY 143 (2.637 Å) and ASN 142 (2.944 Å) like co-crystallized 3WL A (Figure 12b). After analyzing the docking study results, it was observed that all of the studied ligands were placed in the same binding site (green sphere) of 6M2N as the co-crystallized 3WL A and it was observed they have the same orientation as the co-crystallized ligand ( Figure 13).
The study indicates the possibility of using approved drugs in the treatment of coronavirus disease (COVID-19).
The best results were obtained for antiretrovirals: Funding: This paper has been financed through the NUCLEU Program, which is implemented with the support of ANCSI project no. PN 19-41 01 02.