Using thermodynamic integration MD simulation to compute relative protein-ligand binding free energy of a GSK3β kinase inhibitor and its analogs

Hsing Chou Lee, Wen Chi Hsu, An Lun Liu, Chia Jen Hsu, Ying Chieh Sun*

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

28 引文 斯高帕斯(Scopus)

摘要

Thermodynamic integration molecular dynamics simulation was used to investigate how TI-MD simulation preforms in reproducing relative protein-ligand binding free energy of a pair of analogous GSK3β kinase inhibitors of available experimental data (see Fig. 1), and to predict the affinity for other analogs. The computation for the pair gave a ΔΔG of 1.0 kcal/mol, which was in reasonably good agreement with the experimental value of -0.1 kcal/mol. The error bar was estimated at 0.5 kcal/mol. Subsequently, we employed the same protocol to proceed with simulations to find analogous inhibitors with a stronger affinity. Four analogs with a substitution at one site inside the binding pocket were the first to be tried, but no significant enhancement in affinity was found. Subsequent simulations for another 7 analogs was focused on substitutions at the benzene ring of another site, which gave two analogs (analogs 9 and 10) with ΔΔG values of -0.6 and -0.8 kcal/mol, respectively. Both analogs had a OH group at the meta position and another OH group at the ortho position at the other side of the benzene ring, as shown in Table 3. To explore further, another 4 analogs with this characteristic were investigated. Three analogs with ΔΔG values of -2.2, -1.7 and -1.2 kcal/mol, respectively, were found. Hydrogen bond analysis suggested that the additional hydrogen bonds of the added OH groups with Gln185 and/or Asn64, which did not appear in the reference inhibitor or as an analog with one substitution only in the examined cases, were the main contributors to an enhanced affinity. A prediction for better inhibitors should interest experimentalists of enzyme and/or cell assays. Analysis of the interactions between GSK3β kinase and the investigated analogs will be useful in the design of GSK3β kinase inhibitors for compounds of this class.

原文英語
頁(從 - 到)37-49
頁數13
期刊Journal of Molecular Graphics and Modelling
51
DOIs
出版狀態已發佈 - 2014 6月

ASJC Scopus subject areas

  • 光譜
  • 物理與理論化學
  • 電腦繪圖與電腦輔助設計
  • 材料化學

指紋

深入研究「Using thermodynamic integration MD simulation to compute relative protein-ligand binding free energy of a GSK3β kinase inhibitor and its analogs」主題。共同形成了獨特的指紋。

引用此