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In silico identification of new inhibitors for βeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome.
Journal of Molecular Modeling ( IF 2.2 ) Pub Date : 2020-05-26 , DOI: 10.1007/s00894-020-04406-4
Soodeh Mahdian 1 , Mahboobeh Zarrabi 2 , Ashraf Moini 3, 4, 5 , Monireh Movahedi 1 , Maryam Shahhoseini 6, 7, 8
Affiliation  

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.

中文翻译:

在计算机上鉴定作为抗磷脂抗体综合征主要抗原的βeta-2-糖蛋白I新抑制剂。

Beta 2糖蛋白I(β2GPI)是抗磷脂抗体综合症(APS)中存在的自身抗体的主要抗原。β2GPI是具有五个重复域和不同构象的单个多肽。β2GPI的活化J形构象通过第五结构域与膜中带负电荷的磷脂结合,并引起血液凝结反应。我们应用了一种利用虚拟筛选和分子动力学的药物重用策略,以找到针对β2GPI第五域的最佳FDA药物。在第一阶段,通过虚拟筛选选择了具有最有利的ΔG和β2GPI第五域的FDA药物。在这些具有最强ΔG的药物中,选择了Vorapaxar和Antrafenine进行分子动力学(MD)模拟研究。进行了MD模拟以评估Vorapaxar和Antrafenine复合物的稳定性以及这两种药物对蛋白质构象的影响。另外,进行了MD模拟以研究Antrafenine和Vorapaxar对β2GPI与血小板模型膜结合的影响。根据结果​​,Vorapaxar和Antrafenine以良好的结合能结合到蛋白质上(Vorapaxar和Antrafenine结合能分别为-49.641和-38.803 kcal / mol)。在这项研究中,表明与单独的蛋白质和Antrafenine复合物中的蛋白质不同,Vorapaxar复合物中的蛋白质在350 ns后与模型膜完全分离。此外,Vorapaxar导致β2GPI的活化J形发生更多变化。从而,
更新日期:2020-05-26
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