Insights of dietary phytochemicals targeting Parkinson's disease key genes and pathways: A network pharmacology approach

Parkinson's disease (PD) is a complex neurological disease associated with the degeneration of dopaminergic neurons. Oxidative stress is a key player in instigating apoptosis in dopaminergic neurons. To improve the survival of neurons many dietary phytochemicals have gathered significant attention recently. Thus, the present study implements a comprehensive network pharmacology approach to unravel the mechanisms of action of dietary phytochemicals that benefit disease management. The literature search was performed to identify ligands (i.e., comprising dietary phytochemicals and Food and Drug Administration pre-approved PD drugs) in the PubMed database. Targets associated with selected ligands extracted from the STITCH database. Then, the construction of a gene-gene interaction (GGI) network, analysis of hub-gene, functional and pathway enrichment, associated transcription factors, miRNAs, ligand-target interaction network, docking, and molecular dynamics (MD) simulations were performed using different bioinformatics tools. The results of the database search identified 69 ligands and 144 unique targets. GGI and subsequent topological measures indicate histone acetyltransferase p300 (EP300), mitogen-activated protein kinase 1 (MAPK1) or extracellular signal-regulated kinase (ERK)2, and CREB-binding protein (CREBBP) as hub genes. Pathways of neurodegeneration, MAPK signaling, apoptosis, and zinc binding are the key enrichments. hsa-miR-5692a and SCNA gene-associated transcription factors interact with all the 3 hub genes. LTI network indicates rasagiline and baicalein are candidate ligands targeting MAPK1. Moreover, binding affinities and binding free energies of rasagiline and baicalein demonstrated stable binding with Y205, K330, and V173 residues in MAPK1. This study concludes computational molecular insights warrant baicalein and rasagiline as preclinical candidates for PD management.