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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)37-49
Number of pages13
JournalJournal of Molecular Graphics and Modelling
Publication statusPublished - 2014 Jun


  • GSK3β kinase
  • Inhibitor
  • MD simulation
  • Relative binding free energy
  • Thermodynamic integration

ASJC Scopus subject areas

  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Computer Graphics and Computer-Aided Design
  • Materials Chemistry


Dive into the research topics of 'Using thermodynamic integration MD simulation to compute relative protein-ligand binding free energy of a GSK3β kinase inhibitor and its analogs'. Together they form a unique fingerprint.

Cite this