Tubulin Zone Occupancy by PDB-Deposited Colchicine Binding Site Inhibitors

Microtubules are key pharmacological targets in clinical and agricultural contexts. Their dynamic assembly is essential for cell function, making tubulin polymerization a prime target for treating cancer, inflammation, and parasitic diseases, as well as for use as herbicides and fungicides in agricultural applications. The colchicine binding site (COLbs) is among the most studied, known for binding structurally diverse compounds across three zones (Z1-Z3). All colchicine-site ligands bind the central region Z2, with some extending into Z1 or Z3, which differ in hydrophobicity and electronic properties. Here, we analyzed over 160 colchicine-site inhibitors from the Protein Data Bank, using the three-zone classification model to group them by molecular similarity and interaction profiles. This perspective highlights emerging mechanisms for COLbs ligands, including tubulin degradation, with the goal to inform the design of next-generation tubulin polymerization inhibitors.