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Computational Prediction of the Interaction of Ivermectin with Fibrinogen

Vottero et al., Molecular Sciences, doi:10.3390/ijms241411449
Jul 2023  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now with p < 0.00000000001 from 104 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments.
In Silico study showing that ivermectin may bind with high affinity to multiple sites on fibrinogen and may interfere with SARS-CoV-2 spike protein – fibrinogen binding, potentially inhibiting the formation of fibrin clots resistant to degradation (a hallmark of acute COVID-19 and long COVID).
68 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 H7N766, Dengue32,67,68, HIV-168, Simian virus 4069, Zika32,70,71, West Nile71, Yellow Fever72,73, Japanese encephalitis72, Chikungunya73, Semliki Forest virus73, Human papillomavirus52, Epstein-Barr52, BK Polyomavirus74, and Sindbis virus73.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins66,68,69,75, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing33, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination36,76, shows dose-dependent inhibition of wildtype and omicron variants31, exhibits dose-dependent inhibition of lung injury56,61, may inhibit SARS-CoV-2 via IMPase inhibition32, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation5, inhibits SARS-CoV-2 3CLpro49, may inhibit SARS-CoV-2 RdRp activity24, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages55, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation77, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1954,78, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage4, may minimize SARS-CoV-2 induced cardiac damage35,43, increases Bifidobacteria which play a key role in the immune system79, has immunomodulatory46 and anti-inflammatory65,80 properties, and has an extensive and very positive safety profile81.
Vottero et al., 14 Jul 2023, peer-reviewed, 6 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Computational Prediction of the Interaction of Ivermectin with Fibrinogen
Paola Vottero, Scott Tavernini, Alessandro D Santin, David E Scheim, Jack A Tuszynski, Maral Aminpour
International Journal of Molecular Sciences, doi:10.3390/ijms241411449
Hypercoagulability and formation of extensive and difficult-to-lyse microclots are a hallmark of both acute COVID-19 and long COVID. Fibrinogen, when converted to fibrin, is responsible for clot formation, but abnormal structural and mechanical clot properties can lead to pathologic thrombosis. Recent experimental evidence suggests that the spike protein (SP) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly bind to the blood coagulation factor fibrinogen and induce structurally abnormal blood clots with heightened proinflammatory activity. Accordingly, in this study, we used molecular docking and molecular dynamics simulations to explore the potential activity of the antiparasitic drug ivermectin (IVM) to prevent the binding of the SARS-CoV-2 SP to fibrinogen and reduce the occurrence of microclots. Our computational results indicate that IVM may bind with high affinity to multiple sites on the fibrinogen peptide, with binding more likely in the central, E region, and in the coiled-coil region, as opposed to the globular D region. Taken together, our in silico results suggest that IVM may interfere with SP-fibrinogen binding and, potentially, decrease the formation of fibrin clots resistant to degradation. Additional in vitro studies are warranted to validate whether IVM binding to fibrinogen is sufficiently stable to prevent interaction with the SP, and potentially reduce its thrombo-inflammatory effect in vivo.
Author Contributions: Conceptualization, A.D.S., D.E.S. and M.A.; methodology, M.A., P.V. and S.T.; software, P.V., S.T. and M.A.; validation, M.A., P.V., S.T. and A.D.S.; formal analysis, P.V., S.T. and M.A.; investigation, P.V., S.T., M.A. and A.D.S.; resources, J.A.T. and M.A.; data curation, P.V. and S.T.; writing-original draft preparation, P.V. and S.T.; writing-review and editing, D.E.S., A.D.S., M.A., P.V., S.T. and J.A.T.; visualization, P.V. and S.T.; supervision, M.A., A.D.S., D.E.S. and J.A.T.; project administration, M.A. and J.A.T. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: A.D.S. reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO, and grants and personal fees from EISAI. The other authors declare no conflict of interest. Abbreviations The The highest scoring pose of the SP in both states is illustrated in green, the second pose in blue, and the third in orange. The binding pockets where IVM inhibits fibrinogen, which happen to be situated at the interface of SP and fibrinogen, are emphasized as follows: Site 3 and Site 12, both located in the central E region, are highlighted in yellow and dark green, respectively. Meanwhile, the gamma1 site stands out in cyan, and the gamma2 site in purple; Site 3b, as identified by the Site..
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