Identification of Novel β-Tubulin Inhibitors Using a Combined In Silico/In Vitro Approach

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Tubulin inhibitors are promising therapeutic leads for antimitotic and antiparasitic applications.
• Targeting the colchicine binding site of β-tubulin is a key strategy in developing novel anticancer agents.

Purpose of the Study:

• To employ an in silico pharmacophore-based virtual screening approach to identify novel tubulin inhibitors.
• To validate the identified compounds through in vitro tubulin polymerization inhibition assays.

Main Methods:

• Generation of structure- and ligand-based pharmacophore models for known tubulin inhibitors.
• Virtual screening of compound databases against the generated models.
• Experimental validation of prioritized hits using in vitro tubulin polymerization inhibition assays.

Main Results:

• 11 out of 41 tested compounds (26.8% hit rate) were identified as active tubulin polymerization inhibitors.
• Two novel inhibitors exhibited IC50 values comparable to colchicine.
• A potent acetamide-bridged benzodiazepine/benzimidazole derivative showed an IC50 of 2.9 microM.

Conclusions:

• The pharmacophore models are effective tools for discovering diverse inhibitors targeting the tubulin colchicine binding site.
• The identified compounds represent potential leads for developing new cancer therapeutic agents.