Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2
Ahmad F Eweas, Amr A Alhossary, Ahmed S Abdel-Moneim
Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908
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.
AUTHOR CONTRIBUTIONS ASA-M contributed conception of the study and critically revised the manuscript. AFE conducted the molecular docking and wrote the first draft of the manuscript. AAA performed the molecular dynamics simulation. ASA-M, AFE, and AAA shared analyzing and discussing the results. All authors contributed to manuscript revision, read, and approved the submitted version.
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2020. 592908/full#supplementary-material Supplementary Figure 3 | RMSD and number of Hydrogen bonds. For every receptor, the RMSD and Hydrogen bonds number for each ligand were demonstrated.
Conflict of Interest: 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.
References
Abraham, Murtola, Schulz, Páll, Smith et al., GROMACS: high performance molecular simulations through multilevel parallelism from laptops to supercomputers, SoftwareX,
doi:10.1016/j.softx.2015.06.001Baker, Sept, Joseph, Holst, Mccammon, Electrostatics of nanosystems: application to microtubules and the ribosome, Proc. Natl. Acad. Sci. U.S.A,
doi:10.1073/pnas.181342398Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of Covid-19-preliminary report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Cai, Yang, Liu, Chen, Shu et al., Experimental treatment with favipiravir for COVID-19: an open-label control study, Engineering,
doi:10.1016/j.eng.2020.03.007Choy, Wong, Kaewpreedee, Sia, Chen et al., Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro, Antiviral Res,
doi:10.1016/j.antiviral.2020.104786Deshpande, Tiwari, Nyayanit, Modak, In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2, Eur. J. Pharmacol,
doi:10.1016/j.ejphar.2020.173430Eckerle, Becker, Halpin, Li, Venter et al., Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing, PLoS Pathog,
doi:10.1371/journal.ppat.1000896Gao, Yan, Huang, Liu, Zhao et al., Structure of the RNA-dependent RNA polymerase from COVID-19 virus, Science,
doi:10.1126/science.abb7498Glowacka, Bertram, Müller, Allen, Soilleux et al., Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response, J. Virol,
doi:10.1128/JVI.02232-10Gurung, In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors, Gene Rep,
doi:10.1016/j.genrep.2020.100860Hall, Ji, A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease, Travel Med. Infect. Dis,
doi:10.1016/j.tmaid.2020.101646Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Hosein, Moore, Known SARS-CoV-2 infections: the tip of an important iceberg, Int. J. Health Plann. Manage,
doi:10.1002/hpm.3006Ivanov, Thiel, Dobbe, Van Der Meer, Snijder et al., Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase, J. Virol,
doi:10.1128/JVI.78.11.5619-5632.2004Kang, Yang, Hong, Zhang, Huang et al., Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites, Acta Pharm. Sin. B,
doi:10.1016/j.apsb.2020.04.009Kumar, Singh, Patel, In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing, J. Infect. Public Health,
doi:10.1016/j.jiph.2020.06.016Kumari, Kumar, g_mmpbsa-a GROMACS tool for high-throughput MM-PBSA calculations, J. Chem. Inf. Model,
doi:10.1021/ci500020mKwiek, Haystead, Rudolph, Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines, Biochemistry,
doi:10.1021/bi035923wLehrer, Rheinstein, Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2, Vivo,
doi:10.21873/invivo.12134Ma, Wu, Shaw, Gao, Wang et al., Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex, Proc. Natl. Acad. Sci. U.S.A,
doi:10.1073/pnas.1508686112Maier, Martinez, Kasavajhala, Wickstrom, Hauser et al., ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB, J. Chem. Theory Comput,
doi:10.1021/acs.jctc.5b00255Mielech, Chen, Mesecar, Baker, Nidovirus papainlike proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities, Virus Res,
doi:10.1016/j.virusres.2014.01.025Mugisha, Vuong, Puray-Chavez, Kutluay, A facile Q-RT-PCR assay for monitoring SARS-CoV-2 growth in cell culture, bioRxiv,
doi:10.1101/2020.06.26.174698Osipiuk, Jedrzejczak, Tesar, Endres, Stols et al., The crystal structure of papain-like protease of SARS CoV-2, Center for Structural Genomics of Infectious Diseases,
doi:10.2210/pdb6w9c/pdbPettersen, Goddard, Huang, Couch, Greenblatt et al., UCSF chimera-a visualization system for exploratory research and analysis, J. Comput. Chem,
doi:10.1002/jcc.20084Rowland, Chauhan, Fang, Pekosz, Kerrigan et al., Intracellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein: absence of nucleolar accumulation during infection and after expression as a recombinant protein in vero cells, J. Virol,
doi:10.1128/JVI.79.17.11507-11512.2005Shannon, Selisko, Le, Huchting, Touret et al., Favipiravir strikes the SARS-CoV-2 at its achilles heel, the RNA polymerase,
doi:10.1101/2020.05.15.098731Sheahan, Sims, Leist, Schäfer, Won et al., Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV, Nat. Commun,
doi:10.1038/s41467-019-13940-6Siu, Teoh, Lo, Chan, Kien et al., The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles, J. Virol,
doi:10.1128/JVI.01052-08Tay, Fraser, Chan, Moreland, Rathore et al., Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin, Antiviral Res,
doi:10.1016/j.antiviral.2013.06.002Timani, Liao, Ye, Zeng, Liu et al., Nuclear/nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus, Virus Res,
doi:10.1016/j.virusres.2005.05.007Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol. J,
doi:10.1186/1743-422X-2-69Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem. J,
doi:10.1042/BJ20120150Walls, Park, Tortorici, Wall, Mcguire et al., Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein, Cell,
doi:10.1016/j.cell.2020.11.032Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Wang, Wang, Kollman, Case, Automatic atom type and bond type perception in molecular mechanical calculations, J. Mol. Graph. Model,
doi:10.1016/j.jmgm.2005.12.005Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet
Warren, Jordan, Lo, Ray, Mackman et al., Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys, Nature
Wu, Liu, Yang, Zhang, Zhong et al., Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharm. Sin. B
Wu, Peng, Huang, Ding, Wang et al., Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China, Cell Host Microbe
Xu, Liu, Weiss, Arnold, Sarafianos et al., Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design, Nucleic Acids Res
Yan, Zou, Sun, Li, Xu et al., Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model, Cell Res
Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Res,
doi:10.1016/j.antiviral.2020.104760Yin, Mao, Luan, Shen, Shen et al., Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir, Science,
doi:10.1126/science.abc1560Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405Zhao, Jha, Wu, Elliott, Ziebuhr et al., Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology, Cell Host Microbe,
doi:10.1016/j.chom.2012.04.011Zhu, Zhang, Wang, Li, Yang et al., A novel coronavirus from patients with pneumonia in China, N. Engl. J. Med,
doi:10.1056/NEJMoa2001017
