A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Abstract

Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein–ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than −8.0 kcal/mol in the FIXa-grids and higher than −7.5 kcal/mol in the FXa-grids.

Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units

“…The specific alignment of rivaroxaban in the active site allows for the chlorine on the thiophene moiety to interact with the Tyr228 residue in the S1 pocket, mainly through noncovalent halogen-π interactions. This interaction has been described as key for the ligand binding and recognition to the enzyme representing a similar relevance to halogen bond interactions [44,45]. A common halogen-π bond describes the aromatic rings as donors and the C-X bonds (with X = F, Cl, Br, I) as acceptors [46].…”

Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa

“…Blood coagulation plays a crucial role in maintaining hemostasis. However, deviations from normal coagulation can have severe consequences, leading to a range of coagulationassociated disorders [1][2][3]. Among these disorders, atrial fibrillation stands out as a significant contributor, as it promotes the formation of blood clots, thereby precipitating various clinical pathological conditions, including arterial [4] and venous thrombosis [5], heart attacks, ischemic strokes [6], pulmonary embolisms [7], and cardiac strokes [8].…”

“…Among these disorders, atrial fibrillation stands out as a significant contributor, as it promotes the formation of blood clots, thereby precipitating various clinical pathological conditions, including arterial [4] and venous thrombosis [5], heart attacks, ischemic strokes [6], pulmonary embolisms [7], and cardiac strokes [8]. Collectively, these conditions fall under the category of thromboembolic disorders, which continue to pose substantial threats to both mortality and disability rates in the modern era [1][2][3]. In addressing these disorders, anticoagulants have emerged as the established treatment and can effectively manage thromboembolic disorders and improve patient condition.…”

“…Inhibiting specific coagulation factors within the intrinsic pathway has emerged as an appealing target for thromboembolic disorders, offering the potential to reduce the bleeding risk. One such target is factor IXa (FIXa), situated just upstream of factor Xa (FXa) in the downstream propagation of coagulation [3] (Figure S1 in the Supplementary Materials). This strategy hypothesizes and validates the use of selective FIXa inhibitors that can improve bleeding risk profiles while maintaining a similar efficacy to FXa inhibitors.…”

“…This strategy hypothesizes and validates the use of selective FIXa inhibitors that can improve bleeding risk profiles while maintaining a similar efficacy to FXa inhibitors. The underlying principle of this approach lies in selective intrinsic pathway regulation while sparing targets in the extrinsic and common pathways [3].…”