Drug Repurposing by Virtual Screening: Identification of New Already Approved ROCK Inhibitors as Promising Drugs to...

Area of Science:

• Pharmacology
• Neuroscience
• Computational Chemistry

Background:

• ROCK kinases are implicated in neurodegenerative diseases like Alzheimer's disease (AD).
• Targeting ROCK kinases presents a therapeutic strategy for AD treatment.

Purpose of the Study:

• To develop a pharmacophoric map for ROCK inhibitors.
• To identify existing drugs with ROCK inhibitory potential.
• To evaluate the therapeutic promise of identified compounds for AD.

Main Methods:

• Molecular modeling to create a pharmacophoric map of ROCK inhibitors.
• Virtual screening of approved drugs for ROCK1/2 inhibition.
• Molecular dynamics simulations to analyze drug-target interactions.
• Biological assays to confirm safety and efficacy in cellular models.

Main Results:

• Six approved drugs, including ruxolitinib (36) and baricitinib (37), were identified as ROCK inhibitors.
• Ruxolitinib (36) and baricitinib (37) exhibited high potency against ROCK1/2.
• Ruxolitinib (36) showed safety in neuronal and glial cells and reduced glial inflammation markers.
• Tivozanib (39) demonstrated selectivity for ROCK2 over ROCK1.

Conclusions:

• Ruxolitinib (36) is a promising candidate for Alzheimer's disease therapy.
• The study provides a structural basis for designing novel dual JAK-ROCK inhibitors.
• A validated pharmacophoric map aids in the design of new ROCK inhibitors.