Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

Chia Jen Hsu, Wen Chi Hsu, Der Jay Lee, An Lun Liu, Chia Ming Chang, Huei Jhen Shih, Wun Han Huang, Guey Jen Lee-Chen, Hsiu Mei Hsieh-Li, Guan Chiun Lee, Ying Chieh Sun

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)-molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI-MD simulations of the first two compounds (analogs 1 and 2) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3–5) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI-MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.

Original languageEnglish
Pages (from-to)272-281
Number of pages10
JournalChemical Biology and Drug Design
Volume90
Issue number2
DOIs
Publication statusPublished - 2017 Aug 1

Fingerprint

Molecular Dynamics Simulation
Thermodynamics
Molecular dynamics
Assays
Phosphotransferases
Computer simulation
Lead compounds
Drug Discovery
Calibration
Crystal structure
Databases
Derivatives
Pharmaceutical Preparations

Keywords

  • GSK3β kinase
  • MD simulation
  • enzyme assay
  • inhibitor
  • thermodynamic integration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay. / Hsu, Chia Jen; Hsu, Wen Chi; Lee, Der Jay; Liu, An Lun; Chang, Chia Ming; Shih, Huei Jhen; Huang, Wun Han; Lee-Chen, Guey Jen; Hsieh-Li, Hsiu Mei; Lee, Guan Chiun; Sun, Ying Chieh.

In: Chemical Biology and Drug Design, Vol. 90, No. 2, 01.08.2017, p. 272-281.

Research output: Contribution to journalArticle

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