Neuroprotective activities of coixol: <i>in vitro</i> and <i>in silico</i> studies

This study explored coixol, a natural compound from <i>Coix lacryma-jobi</i>, as a potential neuroprotective agent. Coixol’s efficacy was assessed through <i>in vitro</i> assays, molecular docking, and molecular dynamics (MD) simulations, focusing on its effects on acetylcholinesterase (AChE) activity, oxidative stress, and Aβ_1-42 protofibril interactions. Coixol inhibited AChE with an IC₅₀ value of 3.63 ± 1.2 µM and stably interacted with its active site, mimicking tacrine, a known AChE inhibitor. It also protected SH-SY5Y cells against H₂O₂ and Aβ_1-42-induced neurotoxicity in a dose-dependent manner. Gaussian accelerated MD (GaMD) simulations revealed two stable binding modes of coixol with Aβ_1-42 protofibrils. One mode significantly disrupted the protofibril’s structural integrity, explaining coixol’s protective effects. These results highlight coixol’s multi-target therapeutic potential in modulating AChE activity, reducing oxidative stress, and inhibiting Aβ aggregation, offering promising opportunities for neuroprotective drug development.