The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design

FEBS Letters

article

Wu Chengyong¹  Xian Jinghong²  Wang Yanyan³  Xiao Qing-Jie¹  Ma Lingling⁴  Li Yuyan¹  Chen Hai⁴  Lei Qian⁴  Zhang Quan⁵  Sun Bo⁶  Wang Yuxi¹ 

[1] Cancer Center, West China Hospital, Sichuan University;Department of Clinical Research, West China Hospital, Sichuan University;Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University;Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University;State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University;Chinese Academy of Sciences, Shanghai Synchrotron Radiation Facility Science Center, Shanghai Advanced Research Institute

关键词: drug design;    structure–activity relationship;    tubulin;    Vinca-domain ligands;    X-ray crystallography;   

DOI  :  10.1002/1873-3468.14003

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 Asp179 β1 and Asn329 α2 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.

【 授权许可】

Unknown