人體腦部神經元中GSK-3β激酶蛋白過度磷酸化下游蛋白質tau蛋白被認為是引發阿茲海默症可能的病理機制之一。本研究以熱力學積分-分子動力學模擬程序首先計算有實驗結構，及結合能實驗數據的GSK-3β-小分子抑制劑複合體之相對結合自由能，以檢視計算程序是否再現實驗結果，結果得到誤差為 1.3 kcal/mol。為尋找更好的抑制劑分子，我們從已知的抑制劑分子ZRM為基礎，進行官能基轉換，發展ZRM之結構相似物並進行的相對結合自由能的計算。最好的計算結果中，ZRM分子與結構相似物間對於GSK-3β之相對結合自由能為 -0.8 kcal/mol，顯示相似物之抑制能力優於ZRM分子。我們討論置換官能基與預測的結合自由能的關係。這些結果應有助於在計算模擬以及實驗領域中更進一步發展有效的GSK-3β抑制劑。

GSK-3β kinase phosphorylates the downstream protein tau protein. It is thought that, over-phosphorylation of this reaction is one of the pathological mechanisms inducing Alzheimer's disease. In the present study, we calculated the relative binding free energy of GSK-3β-inhibitor complexes using Thermodynamic Integration Molecular Dynamics Simulation and compared it to the experimental result for those complexes of available experimental structures and binding affinity data first in order to investigate how well the computational protocol reproduces experimental data. The computed result was found to deviate from experimental result by 1.3 kcal/mol, showing good agreement. With the computational protocol, we further predict a number of analogs of ZRM ligand in searching for better inhibitors. The best relative binding free energy of GSK-3β-inhibitor complex between ZRM and the analogue is -0.8 kcal/mol, showing better inhibition ability. Substitutions of analogs and their relations with computed relative binding free energy were discussed. These results should be useful for the further development of GSK-3β inhibitors in the areas of computer simulation and experimental assays in the future.

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