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Title 

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

Authors 

N D KimE S ParkY H KimS K MoonS S LeeS K AhnDae Yeul YuK T NoK H Kim

Publisher 

Elsevier

Issue Date 

2010

Citation 

Bioorganic & Medicinal Chemistry, vol. 18, no. 19, pp. 7092-7100

Keywords 

ColchicineMicrotubuleMolecular dockingPharmacophoreVirtual screening

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.

ISSN 

0968-0896

Link 

http://dx.doi.org/10.1016/j.bmc.2010.07.072

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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