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In silico identification of new inhibitors for βeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome

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Abstract

Beta 2 glycoprotein I (β2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). β2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of β2GPI binds to negatively charged phospholipids in the membrane via the fifth domain and causes blood clotting reactions. We applied a drug repurposing strategy using virtual screening and molecular dynamics to find the best FDA drugs against the fifth domain of β2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of β2GPI were selected by virtual screening. Among these drugs that had the most favorable ΔG, Vorapaxar and Antrafenine were selected for molecular dynamics (MD) simulation studies. MD simulation was performed to evaluate the stability of Vorapaxar and Antrafenine complexes and the effect of the two drugs on protein conformation. Also, MD simulation was done to investigate the effect of Antrafenine and Vorapaxar on the binding of β2GPI to the platelet model membrane. According to the results, Vorapaxar and Antrafenine were bound to the protein with the favorable binding energy (Vorapaxar and Antrafenine binding energies are − 49.641 and − 38.803 kcal/mol, respectively). In this study, it was shown that unlike protein alone and protein in the Antrafenine complex, the protein in the Vorapaxar complex was completely separated from the model membrane after 350 ns. Moreover, Vorapaxar led to more changes in the activated J-shape of β2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.

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Acknowledgments

We are very grateful to all those who helped us with this project. We would especially like to thank Mohsen Yazdani (Ph.D. Student of IBB).

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Soodeh Mahdian & Monireh Movahedi

  2. Department of Biotechnology, Biological Faculty, Alzahra University, Tehran, Iran

    Mahboobeh Zarrabi

  3. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Ashraf Moini

  4. Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran

    Ashraf Moini

  5. Department of Gynecology and Obstetrics, Arash Women’s Hospital, Tehran, University of Medical Sciences, Tehran, Iran

    Ashraf Moini

  6. Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Maryam Shahhoseini

  7. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Maryam Shahhoseini

  8. Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran

    Maryam Shahhoseini

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  1. Soodeh Mahdian
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Contributions

S Mahdian collected and interpreted the data and prepared the manuscript. M Zarab trained the methods and participated in data analysis. A Moini contributed to conception and design. M Movahedi revised the manuscript and contributed to design. M Shahhoseini contributed to the design and revision of the manuscript.

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Correspondence to Monireh Movahedi or Maryam Shahhoseini.

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Mahdian, S., Zarrabi, M., Moini, A. et al. In silico identification of new inhibitors for βeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome. J Mol Model 26, 156 (2020). https://doi.org/10.1007/s00894-020-04406-4

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