Polyoxometalates bind multiple targets involved in Alzheimer's disease

Area of Science:

• Neuroscience
• Computational Chemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and Tau tangles.
• Current AD therapies are limited, necessitating the exploration of novel therapeutic agents.
• Polyoxometalates (POMs), a class of inorganic compounds, exhibit potential for AD treatment by interacting with key pathological targets.

Purpose of the Study:

• To investigate the binding potential of POMs to ten critical molecular targets associated with Alzheimer's disease pathogenesis using molecular docking.
• To validate the molecular docking methodology by replicating known POM-target interactions.

Main Methods:

• Utilized molecular docking simulations to predict binding poses and affinities of POMs to AD-related targets.
• Validated the docking approach by comparing predicted binding energies with experimentally determined values for Aβ, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE).

Main Results:

• The molecular docking method was successfully validated against known POM-Aβ, POM-AChE, and POM-BChE interactions.
• POMs demonstrated significant binding affinities to BACE1, PSEN1, PSEN2, APP, APOE4, MAPT (phosphorylation-dependent), and SNCA.
• Predicted binding free energies (ΔG) ranged from -5.28 kcal/mol for MAPT to -10.65 kcal/mol for PSEN1.

Conclusions:

• Molecular docking is a powerful tool for identifying potential POM-based therapeutics for AD.
• POMs have the potential to mitigate key pathological processes in AD, including APP cleavage, Aβ aggregation, and neurotoxicity.
• This study facilitates the discovery and development of novel POM-based treatments for Alzheimer's disease.