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. 2021 Jan 25:11:592908.
doi: 10.3389/fmicb.2020.592908. eCollection 2020.

Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2

Ahmad F Eweas  1   2 , Amr A Alhossary  3 , Ahmed S Abdel-Moneim  4
Affiliations

Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2

Ahmad F Eweas et al. Front Microbiol. .

Abstract

SARS-CoV-2 is a newly emerged coronavirus that causes a respiratory disease with variable severity and fatal consequences. It was first reported in Wuhan and subsequently caused a global pandemic. The viral spike protein binds with the ACE-2 cell surface receptor for entry, while TMPRSS2 triggers its membrane fusion. In addition, RNA dependent RNA polymerase (RdRp), 3'-5' exoribonuclease (nsp14), viral proteases, N, and M proteins are important in different stages of viral replication. Accordingly, they are attractive targets for different antiviral therapeutic agents. Although many antiviral agents have been used in different clinical trials and included in different treatment protocols, the mode of action against SARS-CoV-2 is still not fully understood. Different potential repurposed drugs, including, chloroquine, hydroxychloroquine, ivermectin, remdesivir, and favipiravir, were screened in the present study. Molecular docking of these drugs with different SARS-CoV-2 target proteins, including spike and membrane proteins, RdRp, nucleoproteins, viral proteases, and nsp14, was performed. Moreover, the binding affinities of the human ACE-2 receptor and TMPRSS2 to the different drugs were evaluated. Molecular dynamics simulation and MM-PBSA calculation were also conducted. Ivermectin and remdesivir were found to be the most promising drugs. Our results suggest that both these drugs utilize different mechanisms at the entry and post-entry stages and could be considered potential inhibitors of SARS-CoV-2 replication.

Keywords: COVID-19; SARS-CoV-2; antiviral; chloroquine/hydroxychloroquine; coronavirus disease; favipiravir; ivermectin; remdesivir (GS-5734).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Binding interactions of selected drugs with SARS-CoV-2 spike glycoprotein. (A) chloroquine closed state, (B) chloroquine open state, (C) hydroxychloroquine closed state, (D) hydroxychloroquine, open state, (E) ivermectin closed state, (F) ivermectin, open state (G) remdesivir closed state, (H) remdesivir, open state, (I) favipiravir, closed state, (J) favipiravir, open state.
FIGURE 2
FIGURE 2
Binding interactions of selected drugs with SARS-CoV-2 RNA-dependent RNA polymerase. (A) chloroquine, (B) hydroxychloroquine, (C) ivermectin, (D) remdesivir, and (E) favipiravir.
FIGURE 3
FIGURE 3
Binding interactions of selected drugs with SARS-CoV-2 NSP14. (A) chloroquine, (B) hydroxychloroquine, (C) ivermectin, (D) remdesivir, and (E) favipiravir.
FIGURE 4
FIGURE 4
Binding interactions of selected drugs with SARS-CoV-2 main protease. (A) lopinavir, (B) chloroquine, (C) hydroxychloroquine, (D) ivermectin, (E) remdesivir, and (F) favipiravir.
FIGURE 5
FIGURE 5
Binding interactions of selected drugs with SARS-CoV-2 papain-like protease. (A) lopinavir, (B) chloroquine, (C) hydroxychloroquine, (D) ivermectin, (E) remdesivir, and (F) favipiravir.
FIGURE 6
FIGURE 6
Binding interactions of selected drugs with SARS-CoV-2 M protein. (A) chloroquine, (B) hydroxychloroquine, (C) ivermectin, (D) remdesivir, and (E) favipiravir.
FIGURE 7
FIGURE 7
Binding interactions of selected drugs with SARS-CoV-2 nucleocapsid phosphoprotein. (A) chloroquine, (B) hydroxychloroquine, (C) ivermectin, (D) remdesivir, and (E) favipiravir.
FIGURE 8
FIGURE 8
Ligand/protein complex MD simulation: selected examples. (A) Remdesivir/spike (t = 0): spike closes, (B) Remdesivir/spike (t = 13 ns), the spike opens, and the ligand is still in place, (C) Lopinavir/PLpro (t = 0), the ligand is in place, (D) Lopinavir/PLpro (t = 26 ns), the ligand left the pocket. (E) Remdesivir/PLpro (t = 0), the ligand is in place, (F) Remdesivir/PLpro (t = 23 ns), the ligand moved to the other side of the pocket, (G) Remdesivir/NP (t = 2 ns), the ligand is in the pocket, (H) Remdesivir/NP (t = 21 ns), the pocket is obliterated, and the ligand left the pocket, but it is still attached to the receptor with two hydrogen bonds, and one Pi stacking, (I) Remdesivir/NP (t = 22 ns), the pocket is still obliterated, and the ligand left the pocket, but it is still attached to the receptor with one hydrogen bond. (J) Remdesivir/NP (t = 30), The pocket is open again and the ligand is restored in place.
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