Pharmacophore feature-based virtual screening for finding potent GSK-3 inhibitors using molecular docking and...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Glycogen synthase kinase-3 (GSK-3) is implicated in various diseases, including neurodegenerative disorders.
• Tideglusib, a selective GSK-3 inhibitor, has been explored for treating conditions like Alzheimer's disease.

Purpose of the Study:

• To identify novel, potent, and target-specific inhibitors of GSK-3 using virtual screening.
• To evaluate the binding potential and molecular interactions of identified compounds compared to Tideglusib.

Main Methods:

• Pharmacophore feature-based virtual screening was employed to identify potential GSK-3 inhibitors.
• Molecular dynamics simulations (20-ns) were conducted to validate binding affinities and analyze interactions.

Main Results:

• 64 compounds demonstrated superior GSK-3 binding potential compared to Tideglusib.
• Key molecular interactions, including a covalent interaction with Cys199, were identified at the GSK-3 active site.

Conclusions:

• The study successfully identified promising novel GSK-3 inhibitors with enhanced binding capabilities.
• These findings provide a foundation for developing new targeted therapies for GSK-3-related diseases.