Structure of quercetin 3,4'-dimethyl ether in complex with tubulin provides a rationale for drug design

Yang Su; Wei Yan; Jianhong Yang; Falong Yang

doi:10.1016/j.bbrc.2025.152245

Structure of quercetin 3,4'-dimethyl ether in complex with tubulin provides a rationale for drug design

Biochem Biophys Res Commun. 2025 Jun 23:777:152245. doi: 10.1016/j.bbrc.2025.152245. Online ahead of print.

Authors

Yang Su¹, Wei Yan², Jianhong Yang³, Falong Yang⁴

Affiliations

¹ College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
² Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
³ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yjh1988@scu.edu.cn.
⁴ College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China. Electronic address: falong.yang@swun.edu.cn.

PMID: 40578283
DOI: 10.1016/j.bbrc.2025.152245

Abstract

Microtubules, composed of αβ-tubulin heterodimers, serve as key targets for anticancer therapeutics due to their critical role in cell division. Numerous compounds have been discovered to interact with tubulin and disrupt microtubule dynamics, particularly those targeting the colchicine-binding domain. Certain flavones, for instance, have demonstrated the ability to bind to this site and suppress microtubule polymerization. Despite their potential, progress in developing flavone-based drugs has been limited by insufficient structural data on tubulin-ligand complexes. Here, we present the high-resolution (1.92 Å) crystal structure of tubulin in complex with a flavone derivative, quercetin 3,4'-dimethyl ether (QU34), elucidating the specific molecular interactions at atomic detail. By analyzing this structure alongside other colchicine-site inhibitors, we clarify prior structure-activity relationship (SAR) findings and offer a framework for designing optimized flavone analogs targeting this site.

Keywords: Colchicine domain; Crystal structure; Drug design; Quercetin; Tubulin.