Elucidating the Multi-Targeted Effects of Z-Guggulsterone in Alzheimer’s Disease: Insights from Network Pharmacology and Molecular Docking

Abstract

Z-Guggulsterone (Z-GS) is a natural steroid that has exhibited notable neuroprotective and memory-enhancing effects. In the current bioinformatic analysis, the therapeutic effects of Z-GS against Alzheimer's disease (AD) were investigated using network pharmacology and molecular docking. Initially, the pharmacokinetic profile of Z-GS was assessed following the identification of potential target proteins from various online databases. To elucidate the cellular, molecular, and biological functional implications of the shared targets, GO enrichment and KEGG analysis were utilized to identify the relevant signaling pathways. Furthermore, the PPI network was subjected to functional and topological analyses, leading to the identification of hub targets. Finally, molecular docking was done to validate the interactions between Z-GS and the identified hub targets, providing insights into the binding affinity and interaction modes. The analysis identified ten key genes, BACE1, BCHE, CTSD, PARP2, DRD2, SRD5A1, GRM1, CYP19A1, MAPK3, and TGFBR1, that significantly contribute to the complex AD pathology. In molecular docking, among the screened targets, PARP2 and BChE emerged as the most promising with scores of -10.2 and - 10.3, respectively, highlighting a high propensity for interaction. Although BACE1 also showed a significant binding affinity, scoring -8.6. While remaining targets (MAPK3, CTSD, and CREB) demonstrated weaker binding interactions, with scores of -7.9, -7.7, and -7.3. These key signalling proteins and enzymes contribute significantly to molecular cascades that drive pathological events, cognitive decline, and neurodegeneration. Hence, this integrated analysis prioritized these genes as key targets, suggesting that Z-GS exerts potential therapeutic effects by modulating these critical proteins implicated in AD pathogenesis.