Molecular docking and other computer-related methods are efficient tools broadly used to understand the molecular aspects of protein-ligand interactions during drug discovery against many of previous emerging and fatal diseases including SARS coronavirus [10, 11]. In this study, virtual screening of several FDA-approved/fast-tracked drugs were performed against the SARS-CoV-2 ACE2 host receptor (PDB code = 6M0J), the SARS-CoV-2 3CL protease (PDB code = 1Q2W) and its four active sites, in order to find the most predicated drug-ligand interactions. The presented parameters include the docking scores, ligand binding efficiency and hydrogen bonding interactions. The top ten ranked compounds were selected and presented in Table 1-6 and Figure 1-4. These ten drugs include four antivirals (Favipiravir, Ribavirin, Brincidofovir, and Galidesivir), four anti-malarial (Chloroquine, Mefloquine, Primaquine, and Tafenoquine) and two antimicrobial agents (Doxycycline and Atovaquone). Whether we docked against the ACE2 receptor (PDB code = 6M0J), the SARS-CoV-2 3CL protease (PDB code = 1Q2W) or the four main active sites within the SARS-CoV-2 3CL protease, the docking scores of the 10XC19 drug )Brincidofovir or BCV) shown to be the top hit (ranked #1) compared to the other nine drugs. The docking scores for the BCV were -10.83, -8.30 and -9.02 towards the SARS-CoV-2 3CL protease active site 1 (PDB code = 1Q2W), the SARS-CoV-2 3CL whole protease (PDB code = 1Q2W) (Tables 1-2 and Figure 1-2) and the ACE2 receptor (PDB code = 6M0J) (Tables 3-4 and Figure 3-4), respectively. The antimalarial drug Tafenoquine comes second in the rank where it scored -8.15 and -7.76 with the AC2 receptor and the SARS-CoV-2 3CL protease active site 1, respectively (Table 1 and 3).
Tab. 1 Docking score and energy of the Malaria and Ebola drugs and 1Q2W of COVID-19 with site 1 of COVID-19 Protease (PDB code = 1Q2W)
No.
|
Drug name
|
Score
|
rmsd_refine
|
E_conf
|
E_place
|
E_score1
|
E_refine
|
E_score2
|
Log P
|
Log P
|
1
|
Atovaquone
|
-6.34
|
2.92
|
60.20
|
-69.94
|
-10.85
|
-32.69
|
-6.34
|
6.48
|
6.48
|
2
|
Chloroquine
|
-6.98
|
1.88
|
-42.83
|
-64.37
|
-9.70
|
-22.01
|
-6.98
|
3.98
|
3.98
|
3
|
Doxycycline
|
-7.16
|
0.94
|
46.19
|
-126.91
|
-14.26
|
-38.51
|
-7.16
|
0.46
|
0.46
|
4
|
Mefloquine
|
-6.89
|
0.90
|
119.56
|
-74.76
|
-10.09
|
-33.12
|
-6.89
|
3.91
|
3.91
|
5
|
Primaquine
|
-6.15
|
1.19
|
2.88
|
-70.02
|
-9.23
|
-32.80
|
-6.15
|
2.21
|
2.21
|
6
|
tafenoquine
|
-7.76
|
2.04
|
53.55
|
-57.83
|
-9.67
|
-37.11
|
-7.76
|
5.08
|
5.08
|
7
|
favipiravir
|
-5.29
|
1.27
|
51.65
|
-63.25
|
-9.80
|
-26.76
|
-5.29
|
-0.21
|
-0.21
|
8
|
Ribavirin
|
-5.91
|
1.45
|
150.55
|
-77.89
|
-9.55
|
-28.37
|
-5.91
|
-2.27
|
-2.27
|
9
|
Galidesivir
|
-5.69
|
1.18
|
18.61
|
-74.21
|
-10.14
|
-27.67
|
-5.69
|
-2.34
|
-2.34
|
10
|
Brincidovir
|
-10.83
|
2.88
|
-58.15
|
-51.62
|
-11.43
|
-58.84
|
-10.83
|
5.54
|
5.54
|
Tab. 2 : interaction table between Malaria and Ebola drugs and 1Q2W of COVID-19 with site 1 of COVID-19 Protease (PDB code = 1Q2W)
z
|
Ligand
|
Receptor
|
Interaction
|
Distance
|
E (kcal/mol)
|
Atovaquone
|
6-ring
|
CD PRO 122 (B)
|
pi-H
|
4.11
|
-0.5
|
Chloroquine
|
O 5
|
NZ LYS 5 (A)
|
H-acceptor
|
3.34
|
-0.9
|
6-ring
|
CB LYS 137 (A)
|
pi-H
|
4.16
|
-0.6
|
6-ring
|
CA GLY 2 (B)
|
pi-H
|
3.49
|
-0.5
|
Doxycycline
|
N 6
|
N GLN 127 (A)
|
H-acceptor
|
3.27
|
-3.2
|
Mefloquine
|
O 41
|
OG1 THR 285 (A)
|
H-donor
|
3.09
|
-0.9
|
Primaquine
|
F 1
|
N GLN 127 (B)
|
H-acceptor
|
3.05
|
-0.6
|
6-ring
|
CG LYS 5 (B)
|
pi-H
|
3.72
|
-0.8
|
tafenoquine
|
N 27
|
NH1 ARG 4 (B)
|
H-acceptor
|
3.58
|
-1.6
|
6-ring
|
CD LYS 5 (A)
|
pi-H
|
4.49
|
-0.7
|
favipiravir
|
N 13
|
O LYS 5 (A)
|
H-donor
|
3.16
|
-1.6
|
N 9
|
N GLN 127 (B)
|
H-acceptor
|
3.32
|
-2.3
|
Ribavirin
|
O 1
|
O PHE 3 (B)
|
H-donor
|
2.98
|
-0.8
|
O 15
|
NZ LYS 5 (A)
|
H-acceptor
|
3.26
|
-1.2
|
O 26
|
N GLN 127 (B)
|
H-acceptor
|
3.14
|
-3.2
|
N 27
|
N GLN 127 (A)
|
H-acceptor
|
3.32
|
-2.1
|
5-ring
|
CB LYS 5 (B)
|
pi-H
|
3.99
|
-0.7
|
Galidesivir
|
O 33
|
O PHE 3 (B)
|
H-donor
|
3.00
|
-1.2
|
N 9
|
NH1 ARG 4 (B)
|
H-acceptor
|
3.25
|
-4.0
|
N 12
|
N GLN 127 (A)
|
H-acceptor
|
3.59
|
-1.0
|
6-ring
|
CD LYS 5 (A)
|
pi-H
|
4.39
|
-0.7
|
Brincidovir
|
O 63
|
O GLN 127 (B)
|
H-donor
|
3.02
|
-2.9
|
O 68
|
NH1 ARG 4 (A)
|
H-acceptor
|
2.95
|
-2.4
|
Tab. 3 Docking score and energy of the Malaria and Ebola drugs with ACE-2 Receptor (PDB code = 6M0J)
No.
|
Drug name
|
Score
|
rmsd_refine
|
E_conf
|
E_place
|
E_score1
|
E_refine
|
E_score2
|
Log P
|
1
|
Atovaquone
|
-6.65
|
1.64
|
64.11
|
-76.16
|
-10.05
|
-28.61
|
-6.65
|
6.48
|
2
|
Chloroquine
|
-6.55
|
1.58
|
-38.85
|
-81.75
|
-8.86
|
-30.65
|
-6.55
|
3.98
|
3
|
Doxycycline
|
-7.11
|
3.84
|
47.57
|
-117.63
|
-11.62
|
-44.11
|
-7.11
|
0.46
|
4
|
Mefloquine
|
-6.38
|
1.95
|
120.39
|
-78.94
|
-12.26
|
-28.38
|
-6.38
|
3.91
|
5
|
Primaquine
|
-6.10
|
1.44
|
5.46
|
-77.03
|
-9.45
|
-30.29
|
-6.10
|
2.21
|
6
|
tafenoquine
|
-8.15
|
1.57
|
52.07
|
-101.66
|
-9.88
|
-44.36
|
-8.15
|
5.08
|
7
|
favipiravir
|
-4.63
|
1.17
|
49.20
|
-63.61
|
-9.14
|
-21.46
|
-4.63
|
-0.21
|
8
|
Ribavirin
|
-5.55
|
1.04
|
148.09
|
-80.63
|
-9.69
|
-27.83
|
-5.55
|
-2.27
|
9
|
Galidesivir
|
-5.78
|
1.35
|
18.31
|
-73.22
|
-11.53
|
-25.24
|
-5.78
|
-2.34
|
10
|
Brincidovir
|
-9.02
|
2.19
|
-52.46
|
-57.61
|
-8.93
|
-49.64
|
-9.02
|
5.54
|
Tab. 4 : interaction table between Malaria and Ebola drugs with ACE-2 Receptor (PDB code = 6M0J)
Drug
|
Ligand
|
Receptor
|
Interaction
|
Distance
|
E (kcal/mol)
|
Atovaquone
|
6-ring
|
CA VAL 209 (A)
|
pi-H
|
3.90
|
-1.0
|
Chloroquine
|
N 17
|
O GLU 208 (A)
|
H-donor
|
3.16
|
-0.6
|
CL 1
|
NZ LYS 94 (A)
|
H-acceptor
|
3.45
|
-0.9
|
6-ring
|
CA VAL 209 (A)
|
pi-H
|
4.40
|
-0.5
|
6-ring
|
CG1 VAL 209 (A)
|
pi-H
|
4.14
|
-0.6
|
6-ring
|
N ASN 210 (A)
|
pi-H
|
3.62
|
-0.6
|
Doxycycline
|
O 24
|
OE1 GLU 208 (A)
|
H-donor
|
3.01
|
-1.8
|
6-ring
|
CG2 VAL 209 (A)
|
pi-H
|
4.28
|
-0.7
|
Mefloquine
|
N 29
|
O ASN 210 (A)
|
H-donor
|
2.91
|
-0.7
|
N 29
|
N ASN 210 (A)
|
H-acceptor
|
3.33
|
-0.5
|
6-ring
|
CB GLU 208 (A)
|
pi-H
|
4.42
|
-0.5
|
6-ring
|
CG2 VAL 209 (A)
|
pi-H
|
4.46
|
-0.6
|
Primaquine
|
6-ring
|
CG1 VAL 209 (A)
|
pi-H
|
4.24
|
-0.7
|
6-ring
|
CG1 VAL 209 (A)
|
pi-H
|
4.52
|
-0.7
|
tafenoquine
|
No measured interaction
|
favipiravir
|
O 12
|
NZ LYS 94 (A)
|
H-acceptor
|
3.12
|
-3.5
|
Ribavirin
|
O 15
|
NZ LYS 562 (A)
|
H-acceptor
|
3.03
|
-3.6
|
Galidesivir
|
N 14
|
O ASN 210 (A)
|
H-donor
|
3.05
|
-1.0
|
O 29
|
CE LYS 562 (A)
|
H-acceptor
|
3.16
|
-0.7
|
5-ring
|
CA VAL 209 (A)
|
pi-H
|
3.79
|
-2.1
|
6-ring
|
CA VAL 209 (A)
|
pi-H
|
4.40
|
-0.5
|
5-ring
|
N ASN 210 (A)
|
pi-H
|
4.25
|
-2.7
|
6-ring
|
ND2 ASN 210 (A)
|
pi-H
|
4.58
|
-1.3
|
Brincidovir
|
O 63
|
OE2 GLU 208 (A)
|
H-donor
|
2.79
|
-6.4
|
O 74
|
NE2 GLN 98 (A)
|
H-acceptor
|
3.01
|
-1.2
|
Brincidofovir (BCV) is an orally bioavailable, long-acting, nucleotide analog broad-spectrum antiviral developed by Chimerix Inc. of Durham, North Carolina, USA for the treatment of double-stranded DNA (dsDNA) viruses [17]. BCV is less toxic with an enhanced cellular penetration prodrug of cidofovir wherein the cidofovir acyclic nucleoside monophosphate conjugated through its phosphonate group to a lipid, 3-(Hexadecyloxy)-1-propanol [18]. Being linked to a lipid particle, the compound ensures better and higher intracellular releases of cidofovir and lower plasma concentrations of the active drug, effectively increasing its antiviral activity. When intracellular, the released free cidofovir from the BCV is phosphorylated to its active metabolite cidofovir diphosphate which due to its structural similarity to the deoxycytidine triphosphate (dCTP) nucleotides it gets incorporated into the growing viral DNA strands [19]. Once incorporated, it prevents further DNA polymerization and disrupts DNA replication of viruses. The drug received FDA Fast Track Designation and has been evaluated in healthy individuals in Phase I and Phase II/III clinical trials and revealed to be well-tolerated and highly efficacious against adenoviruses, BK virus, herpes simplex viruses, and smallpox but eventually somehow failed for cytomegalovirus [20, 21]. Preliminary in vitro tests have also shown the drug potential for Ebola virus disease treatment, despite that Ebola is an RNA virus, albeit trials eventually discontinued [22]. Being acted on the Ebola RNA virus before, it is encouraging to act as well on the novel RNA SARS-CoV-2 today. And in addition to its intracellular therapeutic strategy of arresting the viral replication and packaging, our study shows here that it also interferes efficiently with the SARS-CoV-2 ACE2 receptor revealing a different therapeutic mode of action through potentially blocking or inhibiting the virus entry to the host cell, thereby slowing the progression of the infection.
The second top-ranked drug is Tafenoquine which is an orally-active 8-aminoquinoline, a long-acting analog of primaquine, anti-malarial medicine developed by GlaxoSmithKline and 60 Degrees Pharmaceuticals [23, 24]. The drug was FDA-approved for the radical cure of Plasmodium vivax (P. vivax) malaria and the prophylaxis of malaria in 2018. The drug is active against pre-erythrocytic, erythrocytic forms and the gametocytes of Plasmodium species that include P. falciparum and P. vivax [23, 24]. Clinical trials for this drug may be also recommended. Chloroquine, which is an anti-malaria and immunosuppressive drug, recently shown to improve the outcomes in patients with the novel coronavirus pneumonia which made the FDA issue an Emergency Use Authorization to be tested as a treatment for COVID-19, ranked at the fourth position in this study [25].
Lastly, while we were working in this research, an Australian study showed that Ivermectin, an anti-parasitic drug, to be effective against the COVID-19 disease although, further clinical trials are underway to confirm this effectiveness [26]. We decided to do some investigations using molecular docking to check the binding interaction between Ivermectin and the SARS-CoV-2 protease and receptor. We got comparable data to the antiviral Brincidofovir where the docking scores were -10.31 and -8.84 with the SARS-CoV-2 protease and ACE2 receptor, respectively. But overall, Brincidofovir is superiorly recommended because for its high lipophilicity “5.54” where Ivermectin “2.01”.
Tab. 5 Docking score and energy of Ivermectin drug and 1Q2W of COVID-19 with site 1 of COVID-19 Protease (PDB code = 1Q2W)
|
|
Lvermectin
|
S
|
rmsd_refine
|
E_conf
|
E_place
|
E_score1
|
E_refine
|
E_score2
|
Log P
|
B1a
|
-10.90
|
1.73
|
85.45
|
-72.26
|
-8.53
|
-57.13
|
-10.90
|
2.10
|
B1B
|
-10.31
|
1.29
|
89.61
|
-102.28
|
-9.56
|
-53.44
|
-10.31
|
1.59
|
|
|
|
|
|
|
|
|
|
Tab. 6 Docking score and energy of Ivermectin drug with ACE-2 Receptor (PDB code = 6M0J)
|
|
Lvermectin
|
S
|
rmsd_refine
|
E_conf
|
E_place
|
E_score1
|
E_refine
|
E_score2
|
Log p
|
B1a
|
-8.84
|
2.25
|
34.89
|
-62.74
|
-7.46
|
-52.54
|
-8.84
|
2.10
|
B1B
|
-8.62
|
3.56
|
60.89
|
2.73
|
-7.05
|
-47.16
|
-8.62
|
1.59
|
In conclusion, molecular modeling tools were used to screen for potential anti- SARS-CoV-2 therapeutic agents. After a virtual screening against SARS-CoV-2 protease and ACE2 receptor, a set of antivirals, antimalarials, and antimicrobials drugs showed a potent binding interaction, wherein Biocidofovir showed to be the top hit. Therefore, repurposing of Biocidofovir against the COVID-19 disease is suggested.