A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation

Abstract

Background: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses.

Methods: We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration.

Results: Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control.

Conclusion: Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.

Keywords: Atrial fibrillation; Enzyme level; Gene expression; MD simulation; PON1.

Fig. 1

Binding interaction of protein and direct oral anticoagulants. A) Predicted PON1 protein structure, B) Two dimensional interactions of PON1 with apixaban, C) Two dimensional interactions of PON1 with dabigatran, and D) Two dimensional interactions of PON1 with rivaroxaban

Fig. 2

Molecular dynamics simulation trajectories. Root mean square deviation (A) and root mean square fluctuation (B) of apo-PON1 (Black) and complexes (rivaroxaban (Red) and dabigatran (Green) for the time scale of 100 ns

Fig. 3

Molecular dynamics simulation trajectories. Solvent accessible surface area (A) and radius of gyration (B) of apo-PON1 (Black), PON1 with rivaroxaban (Red), and PON1 with dabigatran (Green)

Fig. 4

Molecular dynamics simulation trajectories. Hydrogen bonds of apo-PON1 (Black) and the complexes (rivaroxaban with PON1 (Red) and dabigatran with PON1 (Green)) structures

Fig. 5

Relative expression of PON1. A) Relative quantification of PON1 gene expression in healthy control, rivaroxaban, and dabigatran treated participants. B) Influences of PON1 enzyme activity in normal healthy control, rivaroxaban, and dabigatran treated AF participants