Repurposing existing drugs for new AMPK activators as a strategy to extend lifespan: a computer-aided drug discovery...

Area of Science:

• Biochemistry and Molecular Biology
• Gerontology
• Pharmacology

Background:

• Dietary restriction extends lifespan by activating AMP-activated protein kinase (AMPK), an ATP/AMP sensor.
• Aging diminishes AMPK sensitivity, leading to cellular energy imbalance and associated functional decline.
• AMPK signaling regulates critical cellular processes including autophagy, stress resistance, and inflammation.

Purpose of the Study:

• To identify safe, FDA-approved drugs that can activate AMPK through drug repurposing.
• To discover novel therapeutic applications for existing medications targeting AMPK pathways.
• To explore compounds that can restore cellular energy balance and counteract aging-related AMPK dysfunction.

Main Methods:

• Virtual screening of 1908 FDA-approved drugs for potential AMPK activators.
• Detailed inspection of ligand-protein interactions to assess drug-target engagement.
• Molecular mechanics with the Poisson-Boltzmann and Solvent Accessible Surface Area (MM/PBSA) analysis to evaluate binding affinities at specific AMPK sites (γ and αβ).

Main Results:

• Several FDA-approved drugs were identified as potential AMPK activators through virtual screening.
• Cangrelor, Nacitentan, Levoleucovorin, and Glisoxepide exhibited favorable binding affinities, suggesting higher potential as AMPK activators.
• Compounds binding to the αβ site showed less favorable binding affinities compared to the γ site.

Conclusions:

• The study successfully identified potential AMPK-activating drugs through a repurposing strategy.
• Findings provide a valuable foundation for developing new therapeutic interventions targeting AMPK for aging and metabolic disorders.
• The identified compounds offer promising avenues for future research into AMPK modulation and its role in healthspan extension.