Iranian Journal of Chemistry

Iranian Journal of Chemistry

The role of activator protein INCENP in selective inhibition of Aurora kinase B by Hesperadin

Document Type : Original Article

Authors
Navid Mogharrab 1
Tayebeh Seyedi 2
Leila Navapour 1
1 Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
2 Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
10.22036/cr.2024.443826.1238
Abstract
Aurora kinases A and B have attracted increasing attention as new therapeutic targets for various types of cancers. However, high sequence and structural similarity in their active sites has been a challenge for the design of selective inhibitors. Hesperadin, an ATP-competitive inhibitor, exhibits approximately 4-fold greater selectivity towards Aurora kinase B compared to Aurora kinase A. Here, the structural mechanism underlying Hesperadin's selective inhibition of human Aurora kinase B over Aurora kinase A was investigated using molecular modelling and molecular dynamics simulation. The simulation results demonstrated that Hesperadin forms hydrogen bonds with alanine 157 and glutamate 155 within the hinge region of Aurora kinase B. Additionally, the piperidine ring of Hesperadin interacts with glycine 848, leucine 851 and serine 852 of the INCENP protein (activator of Aurora kinase B) through van der Waals forces. Conversely, no stable hydrogen bonds were observed between Hesperadin and Aurora kinase A in this region, and the inhibitor has no direct interaction with the activator protein (TPX2). These observations suggest that interactions between INCENP and Hesperadin likely play a crucial role in precise positioning of Hesperadin within the active site, enabling sustained and selective binding of the inhibitor with Aurora kinase B. Therefore, it is suggested to pay special attention to the role of activating protein in designing selective inhibitors for Aurora kinase B.

Graphical Abstract

The role of activator protein INCENP in selective inhibition of Aurora kinase B by Hesperadin
Keywords
Anticancer drug
Aurora kinase
Hesperadin
INCENP
Molecular dynamics simulation

Subjects

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Iranian Journal of Chemistry
Volume 6, Issue 2 - Serial Number 11
December 2023
Pages 180-188

  • Receive Date 05 March 2024
  • Revise Date 13 June 2024
  • Accept Date 01 July 2024