Identification of novel and potent small-molecule inhibitors of tubulin with antitumor activities by virtual screening and biological evaluations

被引:0
|
作者
Guangpu Liu
Yang Jiao
Chunxi Huang
Ping Chang
机构
[1] Qilu Hospital of Shandong University,Department of Pharmacy
[2] Shandong Institute for Food and Drug Control,School of Biological Science and Technology
[3] University of Jinan,undefined
来源
Journal of Computer-Aided Molecular Design | 2019年 / 33卷
关键词
Microtubules inhibitors; Anticancer target; Colchicine binding site; Drug discovery; Molecular docking;
D O I
暂无
中图分类号
学科分类号
摘要
Microtubules (made up of α and β-tubulin subunits) play an essential role in the process of mitosis and cell proliferation, thus making them an ideal target for anticancer drugs discovery. Microtubule-targeted drugs, including taxanes and vinca alkaloids, can suppress microtubule dynamics, cause mitotic block and apoptosis, which have been widely used in the treatment of various cancers. There are three unique binding sites (taxanes, vinca alkaloids, and colchicine) in tubulin can be targeted to develop tubulin inhibitors. In this study, we selected the colchicine binding site in tubulin as our target. By performing molecular docking-based virtual screening combined with in vitro tubulin polymerization inhibition assay, we identified two novel and potent tubulin inhibitors (9 and 19). These two compounds arrested cell cycle progression at the G2/M phase and induced apoptosis at sub μM concentrations. In addition, they displayed potent antiproliferative activity with IC50 values in the nM range. Finally, the probable binding modes of 9 and 19 were probed by molecular docking. These two compounds with novel scaffold will shed new light on the lead molecules discovery and the design of new microtubule-targeting agents (MTAs).
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页码:659 / 664
页数:5
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