Network pharmacology and computational-based approaches to activate NRF2 pathway via KEAP1 and GSK-3β inhibition: Exploring the possible molecular insights of mangiferin for Alzheimer's.

Mangifera indica has been utilized as an adjunct therapy for Alzheimer's disease (AD) due to its anti-Alzheimer's phytoconstituents. However, the underlying molecular mechanisms remain largely elusive. This research aimed to investigate the mechanism of action of Mangifera indica phytoconstituents in AD therapy. Anti-Alzheimer's phytoconstituents were identified from the literature and database, their related targets and associated pathways relevant to AD. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualised through Cytoscape software. Target cluster module analysis was performed using the MCODE plugin in Cytoscape. Additionally, Gene Ontology and KEGG analyses were conducted to identify targets associated with Mangifera indica and AD. Furthermore, computational studies were conducted using AutoDock Vina tools, GROMACS, and Gaussian software. In this study, 15 active phytoconstituents and their 157 common targets were analysed. Based on topological parameters such as degree, closeness, and betweenness, the top five targets: Nrf2, Keap1, GSK-3β, APP, and PTPN1 were identified as critical nodes associated with regulation of Nrf2 signalling involving Keap1 and GSK-3β in the context of AD therapy. Molecular docking, MD simulations (1000 ns), PCA, DFT, and MM-PBSA analyses of Nrf2, Keap1, and GSK-3β demonstrated that the compound Mangiferin exhibited favourable predicted binding, stable interaction behaviour, and consistent equilibrium dynamics in comparison with reference ligands. This research highlights that Mangifera indica-related AD therapy involves a complex interplay of multiple phytoconstituents, molecular targets, and signalling pathways and offers significant molecular insights of Mangifera indica into potential antioxidant, anti-inflammatory, and neuroprotective mechanisms relevant to neuronal cells.