Identification of Therapeutic Potential of Hydroxychavicol Against Alzheimer's Disease: An Integrated Network Pharmacology, Molecular Docking, and Dynamic Simulation Study.

Abstract

Alzheimer's disease (AD) is a commonly occurring neurodegenerative disease in elderly and it is a leading cause of dementia worldwide. Hydroxychavicol (HC), a major phenolic component of Piper betle, has prominent anti-inflammatory and antioxidant properties, and studies have found its role in cognition improvement. Here is a systematic approach to deciphering the potential protein targets of HC in AD through network pharmacology and validation from molecular docking and dynamics simulation study. First, the druglikeliness of HC was predicted using the SwissADME analysis, which showed significant druglikeliness. A total of 88 possible target genes between HC and AD were obtained from the Swiss Target Prediction, HIT Version 2, DisGeNET, and GeneCards database. The pathway analysis was carried out using the STRING database which showed several genes including COMT, HSP90AA1, and GAPDH as the top hub genes on the basis of degree. GO and KEGG analyses demonstrated that the core targets were mainly involved in cAMP, PI3K/AkT, HIF1, Rap1, and Calcium signaling pathways. The molecular docking of HC with top hub genes resulted in the highest binding of HC with COMT (-8.9 kcal/mol), GAPDH (-6.7 kcal/mol), and HSP90AA1 (-6.5 kcal/mol) that showed stable binding in the molecular dynamics simulation study. COMT regulates the dopamine levels in the prefrontal cortex and impairment of the COMT is associated with the rapid progression of AD. HSP90, a ubiquitous molecular chaperone, is involved in regulating tau metabolism and Aβ processing and found to be downregulated in AD. GAPDH has been reported as the disease-susceptible gene in AD and its interaction with amyloid precursor protein and NFTs has also been reported. These findings suggest that HC is a promising therapeutic candidate, targeting multiple AD-related pathways, warranting further investigation into its molecular mechanisms and potential for clinical application.