A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase

  • Takayoshi Kinoshita
  • Yusuke Sekiguchi
  • Harumi Fukada
  • Tetsuko Nakaniwa
  • Toshiji Tada
  • Shinya Nakamura
  • Kazuo Kitaura
  • Hiroaki Ohno
  • Yamato Suzuki
  • Akira Hirasawa
  • Isao Nakanishi
  • Gozoh Tsujimoto
Article

Abstract

The detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit α (CK2α), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2α, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2α, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2α. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2α inhibitors.

Keywords

CK2 Isothermal titration calorimeter Crystal structure Molecular dynamics Entropy/enthalpy compensation 

Notes

Acknowledgments

These studies are supported by the Program of Fundamental Studies in Health Science of the National Institute of Biochemical Innovation (NIBIO). The synchrotron radiation experiments were done at the BL6A and BL17A stations in the Photon Factory, and at the BL44XU station in SPring-8 faculty with MX225-HE (Rayonix), which is financially supported by Academia Since and National Synchrotron Radiation Research Center (Taiwan, ROC).

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Takayoshi Kinoshita
    • 1
    • 5
  • Yusuke Sekiguchi
    • 1
  • Harumi Fukada
    • 2
  • Tetsuko Nakaniwa
    • 1
  • Toshiji Tada
    • 1
  • Shinya Nakamura
    • 3
  • Kazuo Kitaura
    • 4
  • Hiroaki Ohno
    • 4
  • Yamato Suzuki
    • 4
  • Akira Hirasawa
    • 4
  • Isao Nakanishi
    • 3
    • 6
  • Gozoh Tsujimoto
    • 4
  1. 1.Graduate School of ScienceOsaka Prefecture UniversitySakaiJapan
  2. 2.Graduate School of Life and Environmental ScienceOsaka Prefecture UniversitySakaiJapan
  3. 3.Department of Pharmaceutical SciencesKinki UniversityHigashi-osakaJapan
  4. 4.Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
  5. 5.Department of Biological science, Graduate School of ScienceOsaka Prefecture UniversitySakaiJapan
  6. 6.Computational Drug Design and Discovery, Department of Pharmaceutical SciencesKinki UniversityHigashi-osakaJapan

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