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

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Abstract

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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Acknowledgements

This research was supported by a grant from the Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (YWJKJJHKYJJ-Q1115).

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Authors and Affiliations

  1. Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhua Xilu, Jinan, 250012, People’s Republic of China

    Guangpu Liu & Ping Chang

  2. Shandong Institute for Food and Drug Control, No. 2749 Xinluo Street, Jinan, 250012, People’s Republic of China

    Yang Jiao

  3. School of Biological Science and Technology, University of Jinan, Jinan, 250022, People’s Republic of China

    Chunxi Huang

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  1. Guangpu Liu
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  2. Yang Jiao
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Correspondence to Ping Chang.

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Liu, G., Jiao, Y., Huang, C. et al. Identification of novel and potent small-molecule inhibitors of tubulin with antitumor activities by virtual screening and biological evaluations. J Comput Aided Mol Des 33, 659–664 (2019). https://doi.org/10.1007/s10822-019-00206-y

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  • DOI: https://doi.org/10.1007/s10822-019-00206-y

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