3 years ago

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

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay
Huei-Jhen Shih, Chia-Ming Chang, Guey-Jen Lee-Chen, Wun-Han Huang, Wen-Chi Hsu, An-Lun Liu, Ying-Chieh Sun, Hsiu Mei Hsieh-Li, Der-Jay Lee, Guan-Chiun Lee, Chia-Jen Hsu
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. GSk3β kinase is an important protein target for several diseases. Finding new small-molecule inhibitors may yield new lead compounds, and spur drug discovery. Based on an existing ligand–GSK3β kinase complex structure, thermodynamic integration MD simulation was utilized to investigate binding for a class of analogous compounds. The binding affinities of three new selected compounds were measured using a kinase assay. This article reports the binding affinities and predicted binding modes of these compounds.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12946

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