Natural flavonoids as prospective inhibitors of human cholinesterase enzymes evaluated through molecular docking

Alzheimer’s disease (AD) represents the most prevalent form of dementia, with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors constituting first-line symptomatic treatment. This study evaluates the inhibitory potential of ten naturally occurring flavonoids—apigenin, chrysin, fisetin, galangin, isorhamnetin, kaempferol, luteolin, myricetin, naringenin, and quercetin—against human AChE and BChE through molecular docking simulations. Results demonstrate that fisetin (FIS), luteolin (LUT), and apigenin (API) exhibit the highest affinity for AChE (lowest Δ G and K i), consistent with their planarity and moderate polarity. For BChE, myricetin (MYR) forms the most stable complex, followed by FIS and LUT, as the wider and more polar active pocket favors highly hydroxylated flavonols. Isorhamnetin (IHN) shows the weakest affinity due to reduced donor–acceptor capacity from 3’-O-methylation. FIS and LUT emerge as dual-target candidates, whereas MYR demonstrates BChE selectivity. These findings identify promising natural scaffolds for developing safer cholinesterase inhibitors with potential therapeutic applications in neurodegenerative diseases, warranting further in vitro and in vivo validation.