Exploring the Potential Mechanism of Action of Ursolic Acid for Parkinson's Disease: An Integrative Network Pharmacology, Docking and Molecular Dynamics Study

Abstract

Parkinson's disease is the second-most prevalent neurological disease globally, affecting about 8.5 million people. Ursolic acid (UA) is a widely distributed pentacyclic triterpenoid compound with various health benefits, including anti-inflammatory, antioxidant, antiviral and anti-tumor properties. Although its anti-Parkinson's activity has been confirmed previously, related mechanisms and pathways of drug action have been studied limited. This study explored possible pathways and used network pharmacology to create a network map of drugs and disease targets. The ADMET profiling was performed to assess the suitability of UA prior to target identification. All the targets were collected and screened through database searches and literature mining. Targeted molecules data were entered into the Cytoscape platform to create a PPI network. Additionally, functional annotation analysis and pathway enrichment were performed. After screening 1520 PD targets and 27 ursolic acid targets, nine targets were identified as overlapping. Through bioinformatics annotation of these overlapping genes, a KEGG pathway gene ontology involving GO biological processes, cellular processes and molecular functions were obtained. From the results, it was observed that UA may exert its effects via the sphingolipid signaling pathway or by activating the cannabinoid receptor, both of which play significant roles in Parkinson's disease. These mechanisms were further supported by molecular docking and dynamics studies. Docking analysis revealed strong binding of UA to the selected target proteins, with ADAM10 exhibiting the highest binding affinity (- 8.4 kcal/mol), surpassing that of the native ligand, levodopa. To evaluate the stability and interaction profile, a 100-ns molecular dynamics simulation was conducted using MOE software, confirming the efficient binding of UA to the Parkinson's disease target ADAM10.

Keywords: Cannabinoid receptor; Molecular docking and dynamics; Network pharmacology; Parkinson’s disease; Sphingolipid pathway; Ursolic acid.