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Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

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机构： [1]Department of Pharmaceutical Engineering, College of Life Science, Northwest Normal University, Lanzhou, Gansu, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China [3]Department of Marine Drug R&D Center, Institute of Oceanography, MinJiang University, Fuzhou, Fujian, China

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关键词： anticancer activity cancer therapy molecular dynamic simulation tubulin inhibitor virtual screening

摘要：

Microtubules play crucial role in process of mitosis and cell proliferation, which have been considered as attractive drug targets for anticancer therapy. The aim of this study was to discover novel and chemically diverse tubulin inhibitors for treatment of cancer. In this investigation, the multilayer virtual screening methods, including common feature pharmacophore model, structure-based pharmacophore model and molecular docking, were developed to screen BioDiversity database with 30,000 compounds. A total of 102 compounds were obtained by the virtual screening, and further filtered by diverse chemical clusters with desired properties and PAINS analysis. Finally, 50 compounds were selected and submitted to the biological evaluation. Among these hits, hits 8 and 30 with novel scaffolds displayed stronger antiproliferative activity on four human tumor cells including Hela, A549, MCF-7, and HepG2. Moreover, the two hits were subsequently submitted to molecular dynamic simulations of 90 ns with the aim of exploring the stability of ligand-protein interactions into the binding pocket, and further probing the mechanism of the interaction between tubulin and hits. The molecular dynamic simulation results revealed there had stronger interactions between tubulin and hits in equilibrium state. Therefore, the hits 8 and 30 have been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity.© 2021 Wiley Periodicals LLC.

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出版当年[2021]版：

大类 | 3 区生物学

小类 | 3 区生化与分子生物学 4 区细胞生物学

最新[2023]版：

大类 | 3 区生物学

小类 | 3 区生化与分子生物学 4 区细胞生物学

第一作者：

第一作者机构： [1]Department of Pharmaceutical Engineering, College of Life Science, Northwest Normal University, Lanzhou, Gansu, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China [*1]Department of Pharmaceutical Engineering, College of Life Science, Northwest Normal University, Lanzhou 730070, Gansu, China.

通讯作者：

通讯机构： [1]Department of Pharmaceutical Engineering, College of Life Science, Northwest Normal University, Lanzhou, Gansu, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China [*1]Department of Pharmaceutical Engineering, College of Life Science, Northwest Normal University, Lanzhou 730070, Gansu, China.

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Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

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