The Mechanism Studying Of Protein Kinase Binding With Its Inhibitors

PDK1 is a serine- threonine kinase, which can activate a number of downstream AGC kinases and the PI3K pathway that is reported in many human cancers. Most of these AGC kinases involved in inhibition of apoptosis, promotion of cell growth and proliferation and glucose uptake and storage are implicated in cancers. As a pivotal kinase for the PI3K pathway and the master regulator of AGC kinase family, PDK1 is a promising anticancer target, and now many small molecular inhibitors of PDK1 have been developed. It is valuable for rational design of novel PDK1 inhibitors to understand the mechanisms of PDK1 protein kinase binding to its known inhibitors.With the rapid development and extensive application of theoretical methods, molecular dynamics (MD) simulations and free energy computation methods et al. have become important tools for exploring protein binding with inhibitors. In this study, we got the structures of PDK1 complexed with inhibitors by molecular docking tests; By using molecular dynamics (MD) simulations and the MM-PBSA method, we got the five dynamics trajectories and the binding free energies; With the MM-GBSA method, we investigated the contributions from all PDK1 residues to the binding free energies on the per-residue basis. Finally, we calculated the hydrogen bonds between PDK1 and the five inhibitors.The residues LEU17, VAL25, SER89, TYR90, ALA91, LEU141 and THR151 et al. had more favorable contributions to bindings, and most of these contributions came from van der Waals terms. The introduced C1-NH2 group significantly enhanced the activity of the inhibitors, and the introduced C2-CH3 group and C3- NH2 group could also enhance the activity by van der Waals interactions or hydrogen bonds. There were two or three hydrogen bonds in each complex, but their occupancies were all lower. We thought this was because the flexibility of the residues forming hydrogen bonds was quite different from their surrounding residues. B-factor analysis and visualization of the trajectories verified our assumption. This implies that the flexible inhibitor structures will be better for the bindings of PDK1 protein kinase with its inhibitors.