Deciphering Glutathione S-Transferase P1 Inhibition Mechanisms for Overcoming Cancer Chemoresistance: Insights From...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Glutathione S-transferase P1 (GSTP1) is vital for detoxifying harmful agents and is implicated in cancer chemoresistance.
• GSTP1 is a significant therapeutic target for developing novel anticancer strategies.
• Ethacrynic acid (EA) is a known inhibitor of GSTP1, but its precise inhibitory mechanisms require elucidation.

Purpose of the Study:

• To investigate the molecular mechanisms by which Ethacrynic acid (EA) and its glutathione conjugate (EA-GSH) inhibit Glutathione S-transferase P1 (GSTP1).
• To analyze the effects of EA and EA-GSH on GSTP1 dimer structure, flexibility, and interactions using molecular dynamics simulations.

Main Methods:

• Comparative molecular dynamics (MD) simulations were performed on four states of GSTP1: apo, holo (GSH-bound), GSTP1-EA complex, and GSTP1-EA-GSH complex.
• Analysis focused on interchain and ligand-enzyme interactions, secondary structure changes, and binding energies at the dimer interface.

Main Results:

• GSTP1 flexibility is primarily governed by the α2 helix movement, crucial for substrate accommodation.
• Ligand binding, particularly by EA, reduced enzyme flexibility and disrupted dynamic coordination within the dimer by altering secondary structures.
• EA binding decreased dimer interface energy, potentially affecting GSTP1's role in apoptosis signaling. GSH conjugation improved EA binding affinity but increased energetic penalties due to solvent exposure.

Conclusions:

• Ethacrynic acid (EA) inhibits GSTP1 by altering its structural dynamics and dimerization, impacting enzymatic and nonenzymatic functions.
• Optimizing the lipophilic/hydrophilic balance of future GSTP1 inhibitors is crucial for effective binding pocket interaction.
• This study provides a structural foundation for designing targeted therapies to enhance cancer chemoresistance treatment.