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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