In silico identification of edible mushroom-derived dual cholinesterase inhibitors as potential therapeutic candidates for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and accounts for approximately 60–70% of dementia cases worldwide. It is characterized by progressive memory impairment, cognitive decline, and neuronal loss. Cholinergic dysfunction, resulting from elevated activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), reduces acetylcholine (ACh) levels and contributes significantly to AD progression. Recent studies have highlighted edible mushrooms as rich sources of bioactive compounds possessing neuroprotective, antioxidant, and anti-inflammatory properties that may support brain health and modulate cholinergic activity. The present study aimed to identify potential mushroom-derived cholinesterase inhibitors using an in-silico screening approach. Twenty-one bioactive metabolites from edible mushrooms were evaluated against AChE (PDB ID: 7E3H) and BuChE (PDB ID: 4BDS) using molecular docking performed with AutoDock 4.2.6. Protein–ligand interactions were further analyzed using UCSF Chimera and BIOVIA Discovery Studio. Among the screened compounds, ergosterol peroxide derived from Inonotus obliquus and ergosterol from Agaricus bisporus exhibited the strongest binding affinities toward both target enzymes, with docking scores ranging from −12.75 to −8.95 kcal/mol and favorable inhibition constants. Interaction analyses revealed stable binding within the catalytic pockets of AChE and BuChE, suggesting their potential as dual cholinesterase inhibitors. These findings indicate that mushroom-derived sterols may serve as promising lead compounds for the development of novel therapeutics against AD. However, further validation through molecular dynamics simulations, in vitro assays, and in vivo studies is necessary to confirm their efficacy, stability, and therapeutic potential.