Citation: DONG Ke-Ke, YANG Xue-Yu, ZHAO Teng-Teng, ZHU Xiao-Lei. Exploring the Selectivity of Tetrahydropyrido[1,2-a]isoindolone Derivatives to GSK3β and CDK5 by Computational Methods[J]. Chinese Journal of Inorganic Chemistry, ;2016, 32(11): 1919-1930. doi: 10.11862/CJIC.2016.263 shu

Exploring the Selectivity of Tetrahydropyrido[1,2-a]isoindolone Derivatives to GSK3β and CDK5 by Computational Methods

1.
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, Nanjing 210009, China

Corresponding author: ZHU Xiao-Lei,
Received Date: 11 May 2016
Available Online: 12 September 2016
Fund Project:

Tetrahydropyrido[1,2-a]isoindolone derivatives are potent inhibitors of glycogen synthase kinase 3β (GSK3β) instead of homologous cyclin-dependent kinase 5 (CDK5). Molecular docking, molecular dynamics simulation, and MM/PBSA energy calculation are utilized to reveal the kinase inhibitors' selective mechanism at the molecular level for improving selectivity. Dynamic cross-correlation map (DCCM) analysis is applied to study the effect of the inhibitor on the interactions between each residue in CDK5 and GSK3β. The results of molecular docking indicate that the binding modes of three inhibitors with two kinases are especially similar, and residues in the binding pockets of two kinases are aligned with each other based on the sequence comparing analysis of crystal structures. The analysis of Root Mean Square Deviation (RMSD) with little fluctuation underlies the stability and reliability of systems. Its values of CDK5 (~0.15 nm) are less than GSK3β (~0.17 nm), and the inhibitor with higher value holds stronger flexibility and conformational changes of kinases. In terms of energies, the electrostatic and van der Walls energies are the major interactions for differentiating the activity between the same inhibitor and two kinases. And the polar solvation energy plays pivotal role in discriminating the selectivity of kinase inhibitor. The residue decomposition indicates that the residues Glu97 and Thr138 of GSK3β are the key residues for differentiating the inhibitor selectivity. On the other hand, in the aspect of inter-residue interaction in one kinase, results indicate that the dynamic correlation of residues is different during the binding process of CDK5 and GSK3β with inhibitors. The correlation of Thr138 in the hinge domain of GSK3β with that of residues Val135~Gln206 is positive, while the correlation of Gln85 and Cys83~Ala150 in CDK5 is unclear, which is a key factor to distinguish inhibitor selectivity.
- tetrahydropyrido[1,2-a]isoindolone derivatives;molecular dynamics simulation;selectivity;stability
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