Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder with complex etiology.
• Enzymes like beta-secretase 1 (BACE-1) and glycogen synthase kinase 3β (GSK-3β) are implicated in AD pathogenesis.
• Simultaneous inhibition of multiple targets offers a promising therapeutic strategy for AD.

Purpose of the Study:

• To establish an optimized virtual ligand screening protocol for identifying multi-target active fragments.
• To discover novel chemical fragments with inhibitory activity against both BACE-1 and GSK-3β.
• To explore the potential of dual BACE-1 and GSK-3β inhibition for Alzheimer's disease treatment.

Main Methods:

• Development and application of a virtual ligand screening protocol.
• Identification of small molecules exhibiting activity against selected enzyme targets.
• Biochemical assays to confirm fragment activity at low-micromolar concentrations.

Main Results:

• A novel fragment was identified with dual activity against BACE-1 and GSK-3β.
• The fragment demonstrated inhibitory activity in the low-micromolar range for both enzymes.
• The identified fragment serves as a promising starting point for developing multi-target AD therapeutics.

Conclusions:

• The virtual screening protocol is effective in identifying multi-target active fragments.
• Dual inhibition of BACE-1 and GSK-3β represents a viable strategy for Alzheimer's disease intervention.
• The presented strategy can be extended to discover inhibitors for other target combinations.