Plasminogen Activator Inhibitors in Thrombosis: Structural Analysis and Potential Natural Inhibitors.

Thrombosis, a critical pathological event characterized by excessive clot formation, is primarily regulated by the fibrinolytic system, where plasminogen activator inhibitors (PAIs) are pivotal. Among them, PAI-1 is the most relevant due to its strong inhibitory effect on fibrinolysis, contributing to various thrombotic disorders. In addition, PAI-2 and PAI-3 have been implicated in distinct physiological and pathological conditions. Understanding their structural and functional characteristics is essential for the development of targeted anticoagulant therapies. This study comprehensively analyzes the secondary and tertiary structures of PAI-1, PAI-2, and PAI-3, highlighting conserved domains and their roles in protein function. Comparative phylogenetic analysis confirms their evolutionary relationships, reinforcing their shared inhibitory mechanisms. Structural superimposition and root-mean-square deviation (RMSD) calculations demonstrate varying degrees of similarity among these inhibitors, with PAI-2 and PAI-3 being more closely related. Furthermore, molecular docking and molecular dynamics simulations were employed to identify natural product-derived inhibitors, focusing on tanshinones and phenolic acids extracted from . Among these compounds, salvianolic acid B and tanshinone IIA sulfate exhibited the highest binding affinity and stability, suggesting their potential as lead compounds for the development of novel fibrinolytic agents. Our findings contribute to understanding PAI structural dynamics and provide insights into natural inhibitor design, paving the way for innovative therapeutic strategies against thrombosis and related disorders.