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The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2

Saha et al., Structural Chemistry, doi:10.1007/s11224-021-01776-0 (date from preprint)
Mar 2021  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 112 treatments. c19ivm.org
In Silico analysis predicting that ivermectin has a large binding affinity for the SARS-CoV-2 spike protein. Three different computer modeling techniques show that ivermectin can inhibit SARS-CoV-2 entrance via hACE2.
70 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N768, Dengue34,69,70, HIV-170, Simian virus 4071, Zika34,72,73, West Nile73, Yellow Fever74,75, Japanese encephalitis74, Chikungunya75, Semliki Forest virus75, Human papillomavirus54, Epstein-Barr54, BK Polyomavirus76, and Sindbis virus75.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins68,70,71,77, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing35, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination38,78, shows dose-dependent inhibition of wildtype and omicron variants33, exhibits dose-dependent inhibition of lung injury58,63, may inhibit SARS-CoV-2 via IMPase inhibition34, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation7, inhibits SARS-CoV-2 3CLpro51, may inhibit SARS-CoV-2 RdRp activity26, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages57, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation79, may interfere with SARS-CoV-2's immune evasion via ORF8 binding2, may inhibit SARS-CoV-2 by disrupting CD147 interaction80-83, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1956,84, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage6, may minimize SARS-CoV-2 induced cardiac damage37,45, increases Bifidobacteria which play a key role in the immune system85, has immunomodulatory48 and anti-inflammatory67,86 properties, and has an extensive and very positive safety profile87.
Saha et al., 1 Mar 2021, preprint, 2 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2
Joyanta Kumar Saha, Md. Jahir Raihan
doi:10.21203/rs.3.rs-160254/v1
In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding a nity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are − 17.8 kcal/mol and − 20.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study con rms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.
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