Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein

Muthusamy et al., Journal of Virology & Antiviral Research, Jul 2021
Ivermectin for COVID-19
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6,300+ studies for 210+ treatments. c19early.org
Meta Analysis
In silico study identifying 32 anti-parisitic compounds effectively inhibiting the RBD of the SARS-CoV-2 spike protein, showing ivermectin and atovaquone among the top compounds.
74 preclinical studies support the efficacy of ivermectin for COVID-19:
34 in silico studies1-34
26 in vitro studies2,35-59
14 in vivo animal studies46,52,59-70
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73, HIV-173, Simian virus 4074, Zika37,75,76, West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
Important missing comments or errors? Let us know.
Study covers ivermectin and atovaquone.
Muthusamy et al., 8 Jul 2021, peer-reviewed, 5 authors.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein
Sathya Muthusamy, Hariprabu Gopal, Thiliban Manivarma, Narayan Satya, Prince. R Pradhan, Prabhu, Prince R Prabhu
The 2019's COVID-19 outbreak which spread to over 200 countries across the globe had its origin from the 2002's SARS-CoV-1 epidemic. The corona viruses are single stranded positive sense RNA viruses with 4 structural proteins such as spike(S), membrane(M), envelope(E) and nucleocapsid(N) proteins and 16 non-structural proteins (NSPs). The spike(S) protein is a homo-trimer protruding from the viral surface comprising 2 subunits namely, the S1 and S2 where the S1 subunit consists of the receptor binding domain (RBD) and the S2 subunit consists of the fusion peptide. The spike glycoprotein is considered as the most desired pharmacological target for drug designing, thus blocking the viral entry into the host. Computer-Aided Drug Designing significantly reduces the cost and time in drug discovery compared to the in-vitro methods. Hence in our study, we have performed a virtual screening of the complete set of anti-parasitic drugs using the popular molecular docking tool, Autodock vina with an aim to repurpose the potential hits for the SARS-CoV-2 infection. The repurposed drugs are advantageous for their easy and immediate access owing to their already proven safety records in toxicity and hence are better than novel drugs. Our results revealed 32 anti-parasitic compounds crossing our threshold binding affinity with selamectin, ivermectin, artefenomel, moxidectin, posaconazole, imidocarb, piperaquine, cepharantine, betulinic acid and atovaquone at the top of the list and occupying the three different electrostatic regions in the RBD. Further optimization strategies and in-vitro trials could make our potential anti-parasitic hits, a potential cure for the SARS-CoV-2 infection.
Conflict of Interest The authors declare no conflict of interest. Author Affiliations Top Department of Biotechnology, Anna University, Chennai--600025
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