Understanding binding between donepezil and human ferritin: molecular docking and molecular dynamics simulation...

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Alzheimer's disease (AD) pathology involves dysregulation of metal ion metabolism.
• Ferritin, an iron-storage protein, plays a crucial role in cellular iron homeostasis and AD.
• Donepezil is a key acetylcholinesterase inhibitor (AChEI) for managing mild to moderate AD symptoms.

Purpose of the Study:

• To investigate the binding interaction between donepezil and human ferritin.
• To elucidate the atomistic mechanisms underlying ferritin stabilization by donepezil.
• To explore the therapeutic implications of ferritin-donepezil interactions in Alzheimer's disease.

Main Methods:

• Structure-based molecular docking of donepezil with human ferritin.
• All-atom molecular dynamics (MD) simulations for 100 ns.
• Principal component and free energy landscape analyses to assess conformational stability and interactions.

Main Results:

• Donepezil binds to ferritin, with the top pose identified through binding affinity.
• MD simulations indicated that donepezil binding stabilizes the ferritin structure.
• The interaction resulted in reduced conformational changes in ferritin upon donepezil binding.

Conclusions:

• Donepezil binding enhances ferritin structural stability, offering an atomistic view of their interaction.
• This study provides insights into the mechanism of protein-drug binding relevant to Alzheimer's disease.
• Understanding the role of iron metabolism and ferritin in AD is clinically significant for developing new therapeutics.