[In silico Search for Tubulin Polymerization Inhibitors]

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Drug Discovery

Background:

• Colchicine is a cytostatic drug used for Familial Mediterranean fever.
• Colchicine exhibits significant side effects, necessitating the search for improved therapeutics.
• Tubulin polymerization is the primary target of colchicine's therapeutic action.

Purpose of the Study:

• To virtually screen compounds structurally related to colchicine.
• To identify novel inhibitors of tubulin polymerization with higher affinity and reduced side effects.
• To provide a basis for the rational design of new cytostatic agents.

Main Methods:

• Virtual screening of 25,745 compounds for tubulin binding affinity.
• Structure-based evaluation of compound interactions with the colchicine binding site on tubulin.
• Identification of compounds with superior binding scores compared to colchicine.

Main Results:

• Eleven commercially available compounds demonstrated higher affinity to tubulin than colchicine.
• Trimethoxybenzene and its derivatives exhibited the highest binding scores.
• These compounds bind to the same site as colchicine, with a similar orientation.

Conclusions:

• The identified compounds represent promising candidates for developing novel cytostatic drugs.
• Trimethoxybenzene derivatives are particularly noteworthy for their potent tubulin inhibition.
• This study provides valuable insights for designing next-generation therapeutics for conditions like Familial Mediterranean fever.