Automated identification of structurally heterogeneous and patentable antiproliferative hits as potential tubulin inhibitors.

By employing a recently developed hierarchical computational platform, we identified 37 novel and structurally diverse tubulin targeting compounds. In particular, hierarchical molecular filters, based on molecular shape similarity, structure‐based pharmacophore, and molecular docking, were applied on a large chemical collection of commercial compounds to identify unexplored and patentable microtubule‐destabilizing candidates. The herein proposed 37 novel hits, showing new molecular scaffolds (such as 1,3,3a,4‐tetraaza‐1,2,3,4,5,6,7,7a‐octahydroindene or dihydropyrrolidin‐2‐one fused to a chromen‐4‐one), are provided with antiproliferative activity in the μ m range toward MCF‐7 (human breast cancer lines). Importantly, there is a likely causative relationship between cytotoxicity and the inhibition of tubulin polymerization at the colchicine binding site, assessed through fluorescence polymerization assays. [ABSTRACT FROM AUTHOR]