Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Computational Chemistry

Background:

• Acetylcholinesterase (AChE) inhibitors are key in Alzheimer's disease (AD) treatment.
• Natural compounds (NCs) offer safer alternatives to synthetic drugs.
• Galantamine and huperzine A exemplify successful plant-derived AChE inhibitors.

Purpose of the Study:

• To virtually screen a large library of natural compounds for AChE inhibitory activity.
• To identify novel, safe, and cost-effective NCs for AD therapy.
• To evaluate the antioxidant potential of selected NCs.

Main Methods:

• Virtual screening using molecular docking of ~150,000 NCs from the ZINC12 database.
• Filtering compounds based on ADME properties and selecting 32 ligands.
• Molecular dynamics simulations (1 μs) to assess complex stability.
• In vitro testing for AChE inhibitory and antioxidant activities.

Main Results:

• Ten compounds formed stable complexes with AChE and were commercially available.
• Five compounds exhibited weak AChE inhibition.
• Three compounds demonstrated significant antioxidant activity.

Conclusions:

• The study identified potential natural compound leads for Alzheimer's disease treatment.
• Compounds with both AChE inhibitory and antioxidant properties warrant further investigation.
• Virtual screening and molecular dynamics are effective for discovering novel drug candidates.