Direct Oral FXa Inhibitors Binding to Human Serum Albumin: Spectroscopic, Calorimetric, and Computational Studies

Abstract

Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research area and provides crucial information about drugs’ pharmacokinetics and pharmacodynamic properties. This research focuses on the study of the interactions between HSA and four commercially available direct oral FXa inhibitors, applying methodologies including steady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and molecular dynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and the complex formation in the ground states affects the fluorescence of HSA, with a moderate binding constant of 104 M−1. However, the ITC studies reported significantly different binding constants (103 M−1) compared with the results obtained through spectrophotometric methods. The suspected binding mode is supported by molecular dynamics simulations, where the predominant interactions were hydrogen bonds and hydrophobic interactions (mainly π–π stacking interactions between the phenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications of the obtained results regarding pathologies such as hypoalbuminemia are briefly discussed.

Activated Factor X delivered by Adeno-Associated virus significantly inhibited bleeding and alleviated hemophilia A/B arthropathy in hemophilia mice

“…The hemostatic e cacy was similar with Xyntha and BeneFIX treated group in hemophilia A and B, respectively. Physiologically, in order to prevent the production of thrombosis, there are many endogenous FXa antagonists in the plasma, such as tissue factor pathway inhibitors and so on, once FXa is formed in the plasma, it will be cleared by antagonists in a short time [25][26][27] . In this stuy, the D-Dimer, a thrombus formation marker was not detectable after AAV-CB-FXaop infusion.…”

Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction

“…Direct FXa inhibitors that are currently commercially available include rivaroxaban, apixaban, edoxaban, and betrixaban, which are an important group of anticoagulants most widely prescribed for the prophylaxis and treatment of thrombotic disorders as a safer alternative to warfarin [ 1 , 2 ]. Their popularity in the market is due to their potency for anticoagulation and their specificity for FXa when administered orally [ 3 ].…”

“…Rivaroxaban and apixaban were the first FXa inhibitors approved by the FDA in 2011 and 2012, respectively. The next molecule, which received marketing authorization in 2015, was edoxaban and then betrixaban two years later [ 1 ]. The pivotal role of FXa in the blood-coagulation pathway makes it an attractive target for anticoagulant drug development [ 7 ].…”

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation

“…Direct oral anticoagulants (DOACs) are an important and a relatively new class of synthetic anticoagulant drugs commonly prescribed for the prevention of venous thrombosis following surgery or during atrial fibrillation, and for the treatment of venous thromboembolism (VTE) [ 1 , 2 , 3 ]. Dabigatran, released in 2010, is a direct thrombin inhibitor.…”