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

摘要

Beta 2 glycoprotein I (beta 2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). beta 2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of beta 2GPI 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 beta 2GPI. In the first phase, FDA drugs that had the most favorable Delta G with the fifth domain of beta 2GPI were selected by virtual screening. Among these drugs that had the most favorable Delta G, 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 beta 2GPI 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 beta 2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.