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Computational Prediction of the Interaction of Ivermectin with Fibrinogen

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. Rece...

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Autores principales: Vottero, Paola, Tavernini, Scott, Santin, Alessandro D., Scheim, David E., Tuszynski, Jack A., Aminpour, Maral
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380762/
https://www.ncbi.nlm.nih.gov/pubmed/37511206
http://dx.doi.org/10.3390/ijms241411449
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author Vottero, Paola
Tavernini, Scott
Santin, Alessandro D.
Scheim, David E.
Tuszynski, Jack A.
Aminpour, Maral
author_facet Vottero, Paola
Tavernini, Scott
Santin, Alessandro D.
Scheim, David E.
Tuszynski, Jack A.
Aminpour, Maral
author_sort Vottero, Paola
collection PubMed
description 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.
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spelling pubmed-103807622023-07-29 Computational Prediction of the Interaction of Ivermectin with Fibrinogen Vottero, Paola Tavernini, Scott Santin, Alessandro D. Scheim, David E. Tuszynski, Jack A. Aminpour, Maral Int J Mol Sci Article 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. MDPI 2023-07-14 /pmc/articles/PMC10380762/ /pubmed/37511206 http://dx.doi.org/10.3390/ijms241411449 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vottero, Paola
Tavernini, Scott
Santin, Alessandro D.
Scheim, David E.
Tuszynski, Jack A.
Aminpour, Maral
Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title_full Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title_fullStr Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title_full_unstemmed Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title_short Computational Prediction of the Interaction of Ivermectin with Fibrinogen
title_sort computational prediction of the interaction of ivermectin with fibrinogen
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380762/
https://www.ncbi.nlm.nih.gov/pubmed/37511206
http://dx.doi.org/10.3390/ijms241411449
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