title: Using thermodynamic integration MD simulation to compute relative protein-ligand binding free energy of a GSK3β kinase inhibitor and its analogs.
abstract: 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.
authors.affiliation: Department of Chemistry, National Taiwan Normal University, 88, TingChow Road Section 4, Taipei 116, Taiwan.
authors.forename: Hsing-Chou
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Chemistry, National Taiwan Normal University, 88, TingChow Road Section 4, Taipei 116, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, 88, TingChow Road Section 4, Taipei 116, Taiwan.
authors.forename: An-Lun
authors.initials: AL
authors.lastname: Liu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, 88, TingChow Road Section 4, Taipei 116, Taiwan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, National Taiwan Normal University, 88, TingChow Road Section 4, Taipei 116, Taiwan. Electronic address: sun@ntnu.edu.tw.
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Sun
mesh_terms: D020134:Catalytic Domain; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D058924:Thienopyridines / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D058924:Thienopyridines; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: GSK3β kinase; Inhibitor; MD simulation; Relative binding free energy; Thermodynamic integration