Identification of vilazodone as a novel plasminogen activator inhibitor to overcome Alzheimer's disease through virtual screening, molecular dynamics simulation, and biological evaluation

Abstract Urokinase‐type plasminogen activator (PLAU), a member of the S1 serine peptidase family in Clan PA, plays a crucial role in the conversion of plasminogen into active plasmin. However, the precise role of PLAU in the central nervous system remains incompletely elucidated, particularly, in relation to Alzheimer's disease (AD). In this study, we successfully identified that PLAU could promote cell senescence in neurons, indicating it as a potential target for AD treatment through a systematic approach, which included both bioinformatics analysis and experimental verification. Subsequently, a structure‐based virtual screening approach was employed to identify a potential PLAU inhibitor from the Food and Drug Administration‐approved drug database. After analyzing docking scores and thoroughly examining the receptor–ligand complex interaction modes, vilazodone emerges as a highly promising PLAU inhibitor. Additionally, molecular docking and molecular dynamics simulations were performed to generate a complex structure between the relatively stable inhibitor vilazodone and PLAU. Of note, vilazodone exhibited superior cytotoxicity against senescent cells, showing a senolytic activity through targeting PLAU and ultimately producing an anti‐AD effect. These findings suggest that targeting PLAU could represent a promising therapeutic strategy for AD. Furthermore, investigating the inhibitory potential and structural modifications based on vilazodone may provide valuable insights for future drug development targeting PLAU in AD disorders.