Dual Targeting of AChE Inhibition and GPX4 Binding by Plant-Derived Compounds for the Treatment of Alzheimer’s Disease: Insights from Molecular Docking and Molecular Dynamics Simulations

Background/Objectives: Alzheimer’s disease (AD) is primarily characterized by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains the mainstay of symptomatic treatment. However, additional hypotheses such as ferroptosis—an iron-dependent form of regulated cell death—have gained prominence in explaining disease progression. Glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme, plays a protective role by suppressing ferroptotic pathways. In this context, identifying phytochemicals capable of inhibiting AChE and exhibiting activator-like binding toward GPX4 may provide a dual therapeutic benefit. This study aimed to identify such dual-acting compounds through a structure-based virtual screening approach. Methods: A total of 3014 natural compounds were collected from three curated databases: NPACT, HIT, and HIM. Molecular docking was performed against GPX4 (7U4I) and AChE (7D9Q). Compounds demonstrating high affinity for both targets were shortlisted. Z-score normalization and statistical ranking were used to select the best two dual-target compounds. Results: Out of 3014 compounds, 68 showed dual-binding potential. Among these, NPACT00189 (docking scores: −6.720 kcal/mol for GPX4; −8.983 kcal/mol for AChE) and NPACT01210 (docking scores: −5.813 kcal/mol for GPX4; −9.640 kcal/mol for AChE) were identified as top candidates based on docking scores. Molecular dynamics (MD) simulations were conducted for both compounds for 250 ns on the AChE binding site and the allosteric site of GPX4. The results indicated that NPACT00189 maintained stable interactions throughout the simulation period at both targets, indicating its dual-targeting potential. Conclusions: NPACT00189 represents a promising dual-target candidate for further investigation in AD therapy. Its potential requires confirmation through comprehensive in vitro and in vivo studies.