Comparative Network Pharmacology and Molecular Docking Analysis of Ursodeoxycholic Acid and Tauroursodeoxycholic Acid in Alzheimer’s Disease-Associated Molecular Networks
TL;DR
Results from approaches examining systems and structure both indicate that ursodeoxycholic acid and tauroursodeoxycholic acid show profiles of action that work together, but they should not be interpreted as direct evidence of therapeutic efficacy in Alzheimer’s disease.
Abstract
Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid- and tau-related pathology, neuroinflammation, metabolic dysregulation, and neuronal loss. Previous studies have shown the potential effects of bile acids, especially ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), on neurodegenerative diseases. However, whether UDCA and TUDCA exhibit distinct molecular interaction patterns within an Alzheimer’s disease-associated biological context remains unclear. This study aims to compare the relevant targets, enrichment pathways, and docking profiles predicted by UDCA and TUDCA using the computer network pharmacology framework. Methods: The study combined analysis of networks relating to drug action with methods examining how structures bind. We predicted potential targets of UDCA and TUDCA by using public databases and intersected with AD-related genes. Protein–protein interaction network construction, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and integrated compound–target–pathway network analysis were performed. Key targets were further evaluated by molecular docking to characterize predicted binding patterns and ligand–target interaction profiles. Results: UDCA and TUDCA share 98 and 103 intersecting genes with AD, respectively, with significant overlapping targets. Functional enrichment analysis showed that UDCA-related targets were significantly enriched in nuclear receptor activity, transcriptional regulation, and metabolic pathways. TUDCA-related targets are more significantly enriched in cell survival, kinase activity and neural activity ligand–receptor interactions. Molecular docking analyses provided target-specific structural information, while same-target docking using GPBAR1 and MAPK14 further revealed ligand-dependent differences in predicted interaction patterns under identical receptor conditions. Results from approaches examining systems and structure both indicate that ursodeoxycholic acid and tauroursodeoxycholic acid show profiles of action that work together. UDCA was associated with predicted upstream regulatory and metabolic-related target profiles, whereas TUDCA showed greater association with intracellular signaling, apoptosis-related, and neuronal survival-related pathways. Conclusions: The two bile acids showed predicted associations with pathways related to cell death regulation, inflammation, and metabolism. These findings provide a methodological basis and testable hypotheses for future experimental validation, but they should not be interpreted as direct evidence of therapeutic efficacy in Alzheimer’s disease.