Integrative Network Pharmacology and Molecular Docking Analysis Uncovers Multi-Target Mechanisms of Alpha-Mangostin...

Alpha-mangostin (AM), a xanthone from Garcinia mangostana, has shown promising nephroprotective properties, but its mechanisms in acute kidney injury (AKI) remain incompletely defined. In this study, we applied an integrative network pharmacology pipeline combined with molecular docking to clarify AM's multi-target mechanisms in AKI. We identified 128 predicted AM targets and intersected them with AKI-related genes, yielding 122 shared targets. Protein-protein interaction analysis identified ten hub genes-TNF, AKT1, IL6, SRC, CTNNB1, HSP90AA1, NFKB1, HIF1A, PPARG, and PTGS2-implicating inflammatory, hypoxia, and cell-survival pathways. KEGG enrichment highlighted HIF-1 signaling, PI3K-Akt signaling, chemokine signaling, AGE-RAGE signaling, and pathways related to cellular senescence and oxidative stress, while GO terms emphasized responses to chemical/oxygen-containing compounds, kinase activity, signal transduction, and apoptosis. Molecular docking against the ten hub proteins showed favorable binding energies across multiple targets. The strongest predicted affinities were observed for PTGS2 (-11.13 kcal/mol), TNF (-9.74 kcal/mol), and AKT1 (-9.48 kcal/mol). Docking positioned AM within the COX-2 catalytic pocket, engaging key catalytic and hydrophobic residues similar to known inhibitors. MD simulation interaction analysis confirmed that AM maintained stable contacts with key human PTGS2 residues, characterized by dominant hydrogen bonds and water-bridge interactions with SER353, TYR355, ARG513, and SER530, along with consistent hydrophobic contacts, and persistent interactions sustained throughout the 200 ns trajectory. Collectively, these results suggest that AM modulates interconnected inflammatory, hypoxic, and survival pathways relevant to AKI, acting as a multi-target ligand with notable interaction involving COX-2, TNF, and AKT1. Further experimental validation and formulation strategies to improve bioavailability are recommended for the advancement of AM toward therapeutic evaluation in AKI.