INTRODUCTION

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by cholinergic dysfunction.

Current FDA-approved acetylcholinesterase (AChE) inhibitors provide only symptomatic benefit and suffer from dose-dependent adverse effects.

The Solution: Dual targeting of AChE and the pro-cognitive a7 nicotinic acetylcholine receptor (a7 nAChR) enables broader, more balanced cholinergic engagement.

METHODS

Step 1: Target Preparation

* Retrieved high-resolution crystal structures for AChE (PDB ID: 4EY7) and a7 nAChR (PDB ID: 4F9W). Binding sites predicted via CB-Dock2.

Step 2: Ligand Repurposing

Identified 15 donepezil analogues via SwissSimilarity using E3FP-based searches of ChEMBL approved drugs.

Step 3: Docking & Profiling Pipeline

Prepared proteins (water removal, Kollman charges, PD8QT format via AutoDock Tools-1.5.7). Energy- minimized via Avogadro and docked using AutoDock Vina. Binding interactions visualized in Discovery Studio; ADME properties assessed via ADMETlab 2.0.

 

RESULTS

Figure 1. Metixene in AChE pocket. Stabilized by aromatic and hydrogen-bond interactions.

 

Figure 2. Metixene in a7 nAChR pocket. Demonstrates superior structural balance compared to Donepezil.

 

Dual-Target & Toxicity Comparison Matrix

CONCLUSIONS

Metixene and Piperidolate emerge as highly promising dual-target leads for AD through balanced engagement of AChE and a7nAChR.

Metixene offers the most balanced engagement and BBB penetration, whereas Piperidolate provides a safer toxicity profile.

This in-silico roadmap successfully demonstrates how structure-based repurposing prioritizes multi-target ligands.

Next Steps: Future in vitro and in vivo validation is required for broader application and clinical translation.