Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents.

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Kim ND, Park ES, Kim YH, Moon SK, Lee SS, Ahn SK, Yu DY, No KT, Kim KH

Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents.

Bioorg Med Chem. 2010 Oct 1;18(19):7092-100. doi: 10.1016/j.bmc.2010.07.072. Epub 2010 Aug 6.

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20810285 [ View in PubMed

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Abstract

Microtubule cytoskeletons are involved in many essential functions throughout the life cycle of cells, including transport of materials into cells, cell movement, and proper progression of cell division. Small compounds that can bind at the colchicine site of tubulin have drawn great attention because these agents can suppress or inhibit microtubule dynamics and tubulin polymerization. To find novel tubulin polymerization inhibitors as anti-mitotic agents, we performed a virtual screening study of the colchicine binding site on tubulin. Novel tubulin inhibitors were identified and characterized by their inhibitory activities on tubulin polymerization in vitro. The structural basis for the interaction of novel inhibitors with tubulin was investigated by molecular modeling, and we have proposed binding models for these hit compounds with tubulin. The proposed docking models were very similar to the binding pattern of colchicine or podophyllotoxin with tubulin. These new hit compound derivatives exerted growth inhibitory effects on the HL60 cell lines tested and exhibited strong cell cycle arrest at G2/M phase. Furthermore, these compounds induced apoptosis after cell cycle arrest. In this study, we show that the validated derivatives of compound 11 could serve as potent lead compounds for designing novel anti-cancer agents that target microtubules.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Podofilox	Tubulin alpha-4A chain	Protein	Humans	Yes	Inhibitor	Details