2. Academic Validation
  3. A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin

  • Molecules. 2021 Feb 10;26(4):946. doi: 10.3390/molecules26040946.
Jinghong Xian 1,  Faqian Bu 1 2,  Yuxi Wang 2,  Fangyi Long 3,  Zhixiong Zhang 2,  Chengyong Wu 1 2,  Yiran Tao 2,  Ting Wang 3,  Guan Wang 1 2
Affiliations

Affiliations

  • 1 Department of Clinical Research Management, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2 Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
PMID: 33579052 DOI: 10.3390/molecules26040946
Abstract

Microtubules composed of α/β tubulin heterodimers are an essential part of the Cytoskeleton of eukaryotic cells and are widely regarded as targets for Cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific Casein Kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

Keywords

IC261; colchicine binding site; crystal structure; drug design; tubulin.

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