Breaking glycolysis: allosteric hotspots for multi-target drug repurposing

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• Glycolysis is crucial for cellular energy, and its enzymes are potential antimicrobial targets.
• Targeting conserved catalytic sites risks host toxicity; allosteric sites offer greater specificity but are hard to find.
• Developing selective antimicrobial strategies is a global health priority.

Purpose of the Study:

• To systematically map allosteric sites across all ten glycolytic enzymes in Staphylococcus aureus and Plasmodium vivax.
• To identify species-specific allosteric targets for selective antimicrobial drug development.
• To explore the potential for polypharmacology by screening FDA-approved compounds against these targets.

Main Methods:

• Employed a multi-scale computational framework integrating elastic network models and residue interaction networks.
• Utilized machine-learning algorithms to systematically map and identify high-confidence allosteric sites.
• Performed virtual screening of 1,615 FDA-approved compounds against identified glycolytic enzyme targets.

Main Results:

• Identified high-confidence allosteric sites in fructose-1,6-bisphosphate aldolase, triosephosphate isomerase, and phosphoglycerate mutase.
• Confirmed species-specific divergence between pathogen and human glycolytic enzymes, supporting selective targeting.
• Discovered multi-target ligands with amphiphilic, interface-stabilizing architectures capable of coordinated glycolytic modulation.

Conclusions:

• A pathway-wide, network-informed approach can effectively identify selective allosteric targets in glycolytic enzymes.
• This strategy enables the rational design of next-generation antimicrobials with improved specificity and reduced host toxicity.
• The identified targets and compounds provide a blueprint for developing novel polypharmacology-based antimicrobial therapies.