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

Ahmad F Eweas,Amr A Alhossary,Ahmed S Abdel-Moneim

doi:10.3389/fmicb.2020.592908

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.

Highlights

SARS-CoV-2 emerged in 2019 as the causative agent of a pneumonia outbreak in Wuhan, Hubei Province, China (Zhu et al, 2020)
In agreement to our findings, ivermectin was found to be docked between the viral spike and the ACE2 receptor (Lehrer and Rheinstein, 2020)
The molecular docking of ivermectin with TMPRSS2 suggested an important role of ivermectin in inhibiting the entry of the virus into the host cell, probably by increasing the endosomal pH

Summary

Introduction

SARS-CoV-2 emerged in 2019 as the causative agent of a pneumonia outbreak in Wuhan, Hubei Province, China (Zhu et al, 2020). The disease outbreak spread globally, causing a pandemic with dozens of millions laboratory-confirmed cases (WHO, 2020) with more folds of the infections could be passed undetected (Hosein et al, 2020). The SARS-CoV-2 genome consists of ∼29.8 kb nucleotides; it possesses 14 open reading frames (ORFs) encoding 27 proteins (Wu A. et al, 2020). The 5 two-thirds of the viral genome encodes the replicase gene. It contains two ORFs: ORF1a and ORF1b. The rest of the genome encodes four structural proteins [spike protein (S protein), envelope protein (E protein), membrane protein (M protein), and nucleocapsid protein (N protein)], in addition to eight accessory proteins (3a/3b, p6, 7a/7b, 8b, 9b, and ORF14) (Wu A. et al, 2020)

Methods

Results

Conclusion