山国武论义在统 http://www edu.cn However, non-ATP-competitive GSK-3 selective inhibitors represent a more efficient pathway for providing real promising drugs for therapeutic intervention. Thiadiazolidinones (TDZDs)and halomethylarylketones(HMKs)were reported as first two families of non-ATP competitive GSK-3 inhibitors and both of them really do not show inhibition on others several kinases as PKA, PKC, CK-2 nd CDK1cyclin B. The privileged scaffold of TDZDs for the selective inhibition of GSK-3 has been revealed based on an extensive SAR study, and two binding modes were then put forward by mapping studies. This information in turn guided an optimization toward the inhibitory activity of TDZD Herein four highly active TDZD and HMK inhibitors 1-4 as depicted in Figure 1 were selected based on structure diversity and a docking study was performed with the published GsK-3B crystal structure(PDB code: 1Q3D)to provide an exquisite understanding of their mechanism of interaction within the non-ATP-binding pocket. The finding of the common properties shared by these pharmacological inhibitors of GSK-3B would be helpful to further optimize these potential drug candidates C O 2 Figure 1. The chemical structures of TDzD and hmK inhibitors 1-4 Materials and methods Molecular docking and structural optimization structures for these four inhibitors were refined using the pm3 method in the mopac 7 and assigned with AMl-BCC partial charges by the QuACPAC program. All partial charges on the atoms of the homology model were derived from AMBEr parameters Docking of the ligands into GSK-3B was performed by using DOCK 5.4. The active site included residues Arg 92 Arg96, Arg180, Lys205 and Tyr216 as recommended by literatures. 5, I7 After docking, MD simulations were carried out by using the CHARMM c33bl program- and a GBSW implicit solvation model- following similar procedures we reported elsewhere. The protein atoms were parameterized by CHARMM-GUl using the CHARMM22 force field.The surface tension coefficient(representing the non-polar solvation energy) was set to 0.03 kcal/mol A),which was consistent with literature precedents in the calculation of non-polar contributions in soluble proteins. 26 All bond lengths involving hydrogen atoms were fixed using the SHAKE algorithm 30.No cutoff for the non-bonded and GB energy calculations was used. In the simulation, temperature was at 300 K. Minimizations were carried out using 1500 steps of steepest descent, followed by Adopted Basis Newton-Raphson(ABNR) minimization until the root mean square gradient was less than 0.001 kcal/mol A. The whole system was then equilibrated for 50 ps, followed by another 10 ns of canonical ensemble (NVT)-MD simulation run. Finally, the ligand-receptor complexes were analyzed by- 2 - However, non-ATP-competitive GSK-3 selective inhibitors represent a more efficient pathway for providing real promising drugs for therapeutic intervention. Thiadiazolidinones (TDZDs) and halomethylarylketones (HMKs) were reported as first two families of non-ATP competitive GSK-3 inhibitors and both of them really do not show inhibition on others several kinases as PKA, PKC, CK-2 and CDK1/cyclin B15-16. The privileged scaffold of TDZDs for the selective inhibition of GSK-3 has been revealed based on an extensive SAR study, and two binding modes were then put forward by mapping studies17-18. This information in turn guided an optimization toward the inhibitory activity of TDZDs. Herein four highly active TDZD and HMK inhibitors 1-4 as depicted in Figure 1 were selected based on structure diversity and a docking study was performed with the published GSK-3β crystal structure (PDB code: 1Q3D)19 to provide an exquisite understanding of their mechanism of interaction within the non-ATP-binding pocket. The finding of the common properties shared by these pharmacological inhibitors of GSK-3β would be helpful to further optimize these potential drug candidates. S N N O CH3 N S H S N O O N S N O O CH3 S Cl O Br Br 1 2 3 4 Figure 1. The chemical structures of TDZD and HMK inhibitors 1-4 Materials and Methods Molecular docking and structural optimization The 3D structures for these four inhibitors were refined using the PM3 method in the MOPAC 7 program 20 and assigned with AM1-BCC partial charges 21-23 by the QuACPAC program. All partial charges on the atoms of the homology model were derived from AMBER 8 parameters. Docking of the ligands into GSK-3β was performed by using DOCK 5.4 24. The active site included residues Arg92, Arg96, Arg180, Lys205 and Tyr216 as recommended by literatures.15, 17 After docking, MD simulations were carried out by using the CHARMM c33b1 program25 and a GBSW implicit solvation model26 following similar procedures we reported elsewhere.27 The protein atoms were parameterized by CHARMM-GUI28 using the CHARMM22 force field 29. The surface tension coefficient (representing the non-polar solvation energy) was set to 0.03 kcal/ (mol·Å2 ), which was consistent with literature precedents in the calculation of non-polar contributions in soluble proteins. 26 All bond lengths involving hydrogen atoms were fixed using the SHAKE algorithm 30. No cutoff for the non-bonded and GB energy calculations was used. In the simulation, temperature was at 300 K. Minimizations were carried out using 1500 steps of steepest descent, followed by Adopted Basis Newton-Raphson (ABNR) minimization until the root mean square gradient was less than 0.001 kcal/mol Å. The whole system was then equilibrated for 50 ps, followed by another 10 ns of canonical ensemble (NVT)-MD simulation run. Finally, the ligand-receptor complexes were analyzed by 中国科技论文在线 http://www.paper.edu.cn