Mapping the Binding Landscape of Allosteric Inhibitor G6PDi-1 on Human G6PD

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Targeting the oxidative pentose phosphate pathway via glucose-6-phosphate dehydrogenase (G6PD) inhibition is a potential anticancer strategy.
• A lack of molecular understanding of G6PD inhibitors hinders drug development.

Purpose of the Study:

• To elucidate the inhibitory mechanism of G6PDi-1, a noncompetitive G6PD inhibitor.
• To provide a molecular basis for developing improved G6PD inhibitors for cancer therapy.

Main Methods:

• Biochemical assays
• Molecular dynamics simulations
• Markov state model analysis
• MM/PBSA binding energy calculations

Main Results:

• G6PDi-1 reduces active G6PD dimer concentration and increases inactive monomer fraction in HepG2 cells.
• Inhibitor binding at the dimer interface sterically blocks oligomerization.
• Binding at distal sites induces allosteric effects, favoring monomeric states.

Conclusions:

• G6PDi-1 inhibits G6PD by disrupting enzyme oligomerization through both direct interface binding and allosteric effects.
• These findings offer a foundation for structure-based design of novel G6PD inhibitors for cancer treatment.