The high‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design
The high‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design
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DOI：
10.1002/1873-3468.14003
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发表时间：
2020-11
期刊：
影响因子：
3.5
通讯作者：
Chengyong Wu;Jinghong Xian;Yanyan Wang;Qing-Jie Xiao;Lingling Ma;Liang Yuyan;C. Hai;Lei Qian;Zhang Quan;Sun Bo;Wan Yuxi
中科院分区：
文献类型：
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作者：
Chengyong Wu;Jinghong Xian;Yanyan Wang;Qing-Jie Xiao;Lingling Ma;Liang Yuyan;C. Hai;Lei Qian;Zhang Quan;Sun Bo;Wan Yuxi
微管蛋白vinca结构域配体可以抑制微管聚合，导致有丝分裂中的细胞死亡，并且已经证明了它们对多种癌症类型的潜力。然而，由于耐药性和毒性，仍然需要开发新的长春花结构域配体。在这项研究中，我们确定了长春瑞滨，YXD和Phomopsin A与微管蛋白复合物在2.5 nm处的高分辨率晶体结构。此外，我们概括了所有先前发表的长春花结合位点的高分辨率晶体结构，以揭示关键残基和长春花结构域配体与微管蛋白相互作用的分子机制。此外，我们还通过引入仲胺基团与Asp179β1和Asn329α2建立盐桥和氢键作用，设计了一系列新颖的三唑并嘧啶衍生物。我们的研究为设计新型微管蛋白长春花结构域配体提供了结构基础。
Tubulin vinca‐domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca‐domain ligands is still needed. In this study, we determined the high‐resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high‐resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca‐domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt‐bridge and H‐bond interactions with Asp179β1 and Asn329α2. Our studies provided the structural basis for designing novel tubulin vinca‐domain ligands.