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An overview of tubulin modulators deposited in protein data bank

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Abstract

Microtubules are cytoskeletal polymers of tubulin and composed of α- and β-tubulin heterodimers, which are regarded as one of the most important, promising and successful targets for chemotherapeutic agents to treat cancer. With more and more tubulin-modulator co-crystal complex structures being solved, the mechanism of action (MOA) of microtubule targeting agents (MTAs) are well understood, which in turn inspired the development of more efficient tubulin modulators. By analyzing the reported tubulin modulators (most of them are inhibitors) that have been co-crystalized with tubulin and deposited in protein data bank (PDB), two new discovered inhibitor binding sites (maytansine and pironetin binding sites) on tubulin are elucidated, while the typical modulator binding sites (colchicine, taxanes, vinca alkaloids, and laulimalid binding sites) are also characterized. Among all the reported tubulin modulators, several inhibitors that bind to taxanes or vinca alkaloids binding sites have been approved by FDA to treat cancer. Thus, tubulin inhibitors discovery and design is still a hotspot in anticancer drug development. In this review, all the reported tubulin modulators that have co-crystal structures with tubulin in PDB are sorted out and classified according to their binding sites in tubulin. Besides, the ease or complexity of developing tubulin inhibitor on different binding sites on tubulin is also discussed. This work could contribute to discovering and designing new potent and specific modulators of tubulin.

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  1. Department of Thyroid and Breast Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, P. R. China

    Haowei Guo & Linlin Zhen

  2. Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, P. R. China

    Xingcong Li

  3. Department of Pediatric Surgery, Huai’an Maternal and Child Health-Care Center, Huai’an, 223002, P. R. China

    Ya Guo

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Guo, H., Li, X., Guo, Y. et al. An overview of tubulin modulators deposited in protein data bank. Med Chem Res 28, 927–937 (2019). https://doi.org/10.1007/s00044-019-02352-2

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