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

作者：Mangiatordi Giuseppe Felice; Trisciuzzi Daniela; Iacobazzi Rosamaria; Denora Nunzio; Pisani Leonardo; Catto Marco; Leonetti Francesco; Alberga Domenico; Nicolotti Orazio^*

来源：Chemical Biology & Drug Design, 2018, 92(1): 1161-1170.

DOI：10.1111/cbdd.13200

• antiproliferative activity
• colchicine binding site inhibitors
• virtual screening

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 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.

• 出版日期2018-7