Integrative computational discovery of a lichen-derived acetylcholinesterase inhibitor candidate for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia worldwide, is a progressive neurodegenerative disorder for which current pharmacological treatments provide only limited symptomatic relief. Human acetylcholinesterase (hAChE) remains one of the most extensively validated therapeutic targets because its inhibition enhances cholinergic neurotransmission and temporarily improves cognitive function. Motivated by the remarkable structural diversity of lichen secondary metabolites, we investigated their potential as novel hAChE inhibitors using an integrated multiscale computational strategy that combined structure-based virtual screening, ADME/Tox profiling, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and MM/GBSA binding free-energy analysis, with donepezil employed as the reference inhibitor. Among the screened compounds, calycin emerged as the most promising candidate. It displayed high predicted binding affinity together with favorable pharmacokinetic characteristics, including high gastrointestinal absorption and blood-brain barrier permeability. Electronic structure analysis revealed greater chemical reactivity and electronic adaptability than donepezil, indicating an enhanced ability to establish stabilizing interactions within the hAChE active site. Molecular electrostatic potential and local reactivity descriptors further identified chemically active regions responsible for favorable non-covalent interactions along the active-site gorge. Long-timescale MD simulations confirmed the structural stability of the hAChE-calycin complex, while MM/GBSA calculations demonstrated a thermodynamically favorable binding process predominantly driven by van der Waals and hydrophobic interactions with key aromatic residues. Collectively, these findings identify calycin as a promising lead scaffold for the development of next-generation hAChE inhibitors and demonstrate the potential of lichen-derived natural products as an underexplored source of chemically diverse candidates for Alzheimer's disease drug discovery.