title: Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay.
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.
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Der-Jay
authors.initials: DJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: An-Lun
authors.initials: AL
authors.lastname: Liu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Huei-Jhen
authors.initials: HJ
authors.lastname: Shih
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Wun-Han
authors.initials: WH
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Hsiu Mei
authors.initials: HM
authors.lastname: Hsieh-Li
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guan-Chiun
authors.initials: GC
authors.lastname: Lee
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ying-Chieh
authors.identifier: 0000-0003-2615-3606
authors.initials: YC
authors.lastname: Sun
mesh_terms: D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta
keywords: GSK3β kinase; MD simulation; enzyme assay; inhibitor; thermodynamic integration