In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Eukaryotic elongation factor 2 kinase (eEF2K) regulates neuronal protein synthesis.
• Dysregulation of eEF2K is implicated in diseases like Alzheimer's disease (AD).
• eEF2K is a potential therapeutic target for neurodegenerative disorders.

Purpose of the Study:

• To identify novel natural product inhibitors of eEF2K.
• To evaluate the therapeutic potential of identified inhibitors for promoting neural differentiation.
• To explore new leads for Alzheimer's disease treatment.

Main Methods:

• Molecular docking of a natural product library (4270 compounds) against eEF2K.
• In vitro evaluation of eEF2 phosphorylation inhibition and protein synthesis promotion.
• Molecular dynamics simulations to assess compound-protein binding stability.

Main Results:

• Compounds 17 and 23 were identified as potent eEF2K inhibitors.
• These compounds suppressed eEF2K activity and increased protein synthesis.
• Compounds 17 and 23 induced neuritogenesis and showed stable binding to eEF2K.

Conclusions:

• Compounds 17 and 23 are novel natural inhibitors of eEF2K.
• These compounds promote neural differentiation, suggesting therapeutic potential for AD.
• The identified compounds represent promising leads for developing treatments for neurodegenerative diseases.