RESUMO
In this work, through a docking analysis of compounds from the ZINC chemical library on human ß-tubulin using high performance computer cluster, we report new polycyclic aromatic compounds that bind with high energy on the colchicine binding site of ß-tubulin, suggesting three new key amino acids. However, molecular dynamic analysis showed low stability in the interaction between ligand and receptor. Results were confirmed experimentally in in vitro and in vivo models that suggest that molecular dynamics simulation is the best option to find new potential ß-tubulin inhibitors. Graphical abstract Bennett's acceptance ratio (BAR) method.
Assuntos
Hidrocarbonetos Policíclicos Aromáticos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Sítios de Ligação , Colchicina/química , Células HeLa , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Bibliotecas de Moléculas Pequenas , Interface Usuário-ComputadorRESUMO
Potential anticancer activity of 16 azetidin-2-one derivatives was evaluated showing that compound 6 [N-(p-methoxy-phenyl)-2-(p-methyl-phenyl)-3-phenoxy-azetidin-2-one] presented cytotoxic activity in SiHa cells and B16F10 cells. The caspase-3 assay in B16F10 cells displayed that azetidin-2-one derivatives induce apoptosis. Microarray and molecular analysis showed that compound 6 was involved on specific gene overexpression of cytoskeleton regulation and apoptosis due to the inhibition of some cell cycle genes. From the 16 derivatives, compound 6 showed the highest selectivity to neoplastic cells, it was an inducer of apoptosis, and according to an in silico analysis of chemical interactions with colchicine binding site of human α/ß-tubulin, the mechanism of action could be a molecular interaction involving the amino acids outlining such binding site.
