Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach
et al., Biotecnia, doi:10.18633/biotecnia.v27.2485, Mar 2025
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
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In silico study showing that ivermectin, the SARS-CoV-2 nucleocapsid (N) protein, and the ORF6 protein share binding sites on human importin α isoforms. Authors used molecular docking to analyze binding affinities between these molecules and various importin α isoforms, finding that all three bind to the ARM2-ARM4 domains (major binding site) with favorable binding energies. Ivermectin may compete with viral proteins for binding to importin α, potentially explaining antiviral activity against SARS-CoV-2. Specifically, ivermectin showed binding affinities to importin α isoforms with free binding energies ranging from -7.71 to -8.63 kcal/mol, comparable to those of viral proteins. This suggests ivermectin could interfere with viral protein transport into the nucleus and inhibit the virus's ability to suppress host interferon-mediated antiviral responses.
74 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 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.
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Gayozo et al., 13 Mar 2025, USA, peer-reviewed, 3 authors.
Contact: elviologo@gmail.com.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach
Biotecnia, doi:10.18633/biotecnia.v27.2485
Ivermectin has been shown in vitro that reduces SARS-CoV-2 replication in infected cells through interactions with importins α, however, the exact mechanism of action is still unknown. The objective of this study was to analyze binding affinities of ivermectin, SARS-CoV-2 nucleocapsid (N) and ORF6 proteins, to isoforms of human importins α using molecular docking methods. Crystallized structures of importins α from Protein Data Bank (PDB) and AlphaFold Protein Structure Database were used, viral proteins were modeled using AlphaFold 2. Molecular docking simulations were performed between human importin α isoforms, ivermectin, N and ORF6 proteins, employing Broyden-Fletcher-Goldfarb-Shanno, FTDock and pyDockRST algorithms. Obtained data evidenced that viral proteins of SARS-CoV-2 and ivermectin showed favorable binding affinities to ARM2-ARM4 domains (major binding site), sharing binding affinities to the same active residues. These results suggest that ivermectin shares the same active site on the α-importins as the SARS-CoV-2 N and ORF6 proteins, demonstrating a potential molecular target for research in the development of new antiviral drugs against COVID-19.
Resulting complexes between importins α isoforms and N protein (NLS pat4 and pat7) showed free binding energy values (∆G) ranging -10.0 to -6.3 kcal.mol -1 , where the NLS pat7 sequence demonstrated the most favorable energy value, specifically to importin α3 and importin α5 (Figure 3 .B, Supplementary Table S1 ). Active residues in complexes formed by N protein and isoforms of α1 subfamily were Phe138, Trp142, Asn146, Ser149, His177, Glu180, Trp184, Asn188, Asn228 in importin α1, and Arg95, Gln100, Glu107, Trp136, Ser143, Glu180, Asn182, Trp231, Glu256, Asp260, Glu266, Asp270, Trp273 in importin α8 , residues that interact with NLS pat4 sequences through hydrogen bonds, unconventional interactions between a polarized carbon atom and hydrogen atom, interactions between Pi orbitals and donors groups of hydrogen bonds. The formation of electrostatic attractions and hydrophobic interactions were also identified (Figure 3 .A,B, Supplementary Figure S2 , Supplementary Figure S3 , Supplementary Table S1 ). Residues Glu107, Trp142, Asn146, Ala176, Glu180, Trp184, Ala222, Tyr225, Trp231, Glu266, Asp270, Trp273 of importin α1, and residues Ser99, Glu101, Pro104, Trp136, Ser143, Arg217, Asp260, Trp263, Glu174, Trp178, Asn182, Trp221, Asn225 of importin α8, interact by hydrogen bonds, carbon hydrogen bonds, Pi interactions with hydrogen bonds donors, hydrophobic and electrostatic interactions with the NLS pat7 sequences (Figure 4 .A,B, Supplementary Figure S2 , Supplementary..
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"abstract": "<jats:p>Ivermectin has been shown in vitro that reduces SARS-CoV-2 replication in infected cells through interactions with importins α, however, the exact mechanism of action is still unknown. The objective of this study was to analyze binding affinities of ivermectin, SARS-CoV-2 nucleocapsid (N) and ORF6 proteins, to isoforms of human importins α using molecular docking methods. Crystallized structures of importins α from Protein Data Bank (PDB) and AlphaFold Protein Structure Database were used, viral proteins were modeled using AlphaFold 2. Molecular docking simulations were performed between human importin α isoforms, ivermectin, N and ORF6 proteins, employing Broyden-Fletcher-Goldfarb-Shanno, FTDock and pyDockRST algorithms. Data obtained evidenced that viral proteins of SARS-CoV-2 and ivermectin showed favorable binding affinities to ARM2-ARM4 domains (major binding site), sharing binding affinities to the same active residues. These results suggest that ivermectin shares the same active site on the α-importins as the SARS-CoV-2 N and ORF6 proteins, demonstrating a potential molecular target for research in the development of new antiviral drugs against COVID-19.</jats:p>",
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