Drug Discovery for Treatment of Pregnancy Compli-cations with APS

Background: Antiphospholipid antibody syndrome (APS or APLS), is an autoimmune disease, caused by antiphospholipid antibodies. APS is associated with pregnancy complications, including preeclampsia, thrombosis, fetal growth restriction, fe-tal loss and recurrent implantation failure. βeta-2-glycoprotein I (β2GPI) is the major antigen for antiphospholipid antibodies and associated with thrombosis. β2GPI is a glycoprotein with five repeated domains. β2GPI exists in different conformations, an open J-shaped conformation, a circular conformation and a S-shape conformation. The fifth domain of J-shaped confor-mation binds to negatively charged phospholipids and causes platelet aggregation and blood clotting reactions.Materials and Methods: Purpose of this study was selection of the best compounds for treatment of APS. For this purpose, bioactive compounds of herbals that were involved in prevent-ing blood coagulation and platelet aggregation, drugs that are prescribed during pregnancy complications and all of the FDA drugs were selected. Based on these compounds, a library was created for studying in silico. Then we applied drug repurposing strategy using virtual screening and molecular dynamics for drug Discovery.Results: In this study, it was shown that the J-shaped of β2GPI was transformed into a s-shaped during the 50 ns. Docking result of drugs that are prescribed during pregnancy against β2GPI’s fifth domain showed that Heparin had a higher ΔG than other drugs that are prescribed during pregnancy. The results shown that folate and warfarin had the highest ΔG after heparin. Eight FDA drugs and Thirteen bioactive compounds had maxi-mum binding negative free-energy change (ΔG) with β2GPI. FDA drugs that were involved in the inhibition of platelet ag-gregation had been considered for molecular dynamics (MD) studies. Also the bioactive compounds that had maximum nega-tive ΔG of interactions with β2GPI’s fifth domain were selected for more accurate studies using MD. Therefore, vorapaxar and antrafenine as FDA drugs and lonchocarpic acid, oleracein C and procyanidin as bioactive compounds were selected for MD studies. Lonchocarpic acid as a bioactive compound of portu-laca oleracea had maximum binding negative ΔG with β2GPI. Based on MD results, lonchocarpic acid complex was more sta-ble than other complexes.Conclusion: Vorapaxar, antrafenine and bioactive compounds of portulaca oleracea might be useful candidates for treatment of antiphospholipid antibody syndrome.

کلیدواژه ها:

Drug Repurposing ، Virtual Screening ، Molecular Dynamics ، Beta-2-Glycoprotein I ، Antiphospholipid Antibody Syndrome