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

Jinghong Xian,Fangyi Long,Yuxi Wang,Zhixiong Zhang,Yiran Tao,Ting Wang,Faqian Bu,Guan Wang,Chengyong Wu

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.

Highlights

Microtubules are intrinsically dynamic polymers, containing two highly homologous proteins—α- and β-tubulin heterodimers, which assemble into protofilaments in a headto-tail form [1,2]
To obtain the precise description of how IC261 interacts with tubulin, we solved the structure of tubulin in complex with IC261 by X-ray crystallography
We found that IC261 can occupy the colchicine-binding site of tubulin, and the interaction between the trimethoxyphenyl group of IC261 and tubulin, as well as the hydrogen bond formed by carbonyl group and the side chain of βAsp249, is important to its inhibitory activity

Summary

Introduction

Microtubules are intrinsically dynamic polymers, containing two highly homologous proteins—α- and β-tubulin heterodimers, which assemble into protofilaments in a headto-tail form [1,2]. As a core component of the eukaryotic cytoskeleton, microtubules are involved in many physiological activities in cells, for instance, the maintenance of cell shape and motility, formation of the spindle during cell mitosis, intracellular material transport during interphase, signal transduction, and other essential processes [3,4]. Being involved in such complex cell activities, microtubules are widely regarded as attractive targets for anticancer chemotherapy, and a large number of small molecule inhibitors that interfere with microtubule dynamics have been discovered. The first four groups are “destabilizing” drugs that inhibit assembly, while the last two groups are the “stabilizing” drugs that inhibit disassembly [5]

Methods

Results

Discussion

Conclusion