Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques

• Published in: Journal of molecular graphics & modelling 2017-03, Vol.72, p.178-186
• Main Authors: Wang, Jing Li, Cheng, Li Ping, Wang, Tian Chi, Deng, Wei, Wu, Fan Hong
• Format: Article
• Language: English
• Subjects: Binding Sites; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - chemistry; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines - chemistry; Protein Kinase Inhibitors - chemistry; Pyrimidines - chemistry; Pyrroles - chemistry; Quantitative Structure-Activity Relationship; Thermodynamics
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2016.12.020

View of superimposed backbone atoms of the final structure of the MD simulation (magenta) and the initial structure (green) for compound 3LXK-42 complex. [Display omitted] •Some new designed JAK3 kinase inhibitors have better inhibitory activity than the most potent Tofacitinib (CP-690550).•This is the first report on MD simulations and binding free energy calculations for CP-690550 derivatives as kinase inhibitors.•3D-QSAR predicted results are in good agreement with the calculated binding free energies results. To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q2) and non-cross-validated correlation coefficient (r2) of the best CoMFA model are 0.715 and 0.992, respectively. The q2 and r2 values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.