UNDERSTANDING THE MOLECULAR MECHANISM OF BINDING MODES OF AURORA A INHIBITORS BY LONG TIME SCALE GPU DYNAMICS

Inhibition of Aurora A kinase interaction is considered to be a promising approach for the discovery of new molecularly targeted cancer therapeutics. In this study, the binding mechanisms of two different inhibitors with a contrasting binding affinity to Aurora A were investigated by long time scale GPU molecular dynamics (MD) simulations coupled with molecular mechanics-Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA) method. The results showed that the predicted binding free energies of these two complexes were consistent with the experimental data. Through analyzing the individual energy components of binding free energy, we found that the van der Waals contribution was the main force to drive the inhibitor-protein binding and the electrostatic contribution was also a crucial factor for the inhibitor-Aurora A binding. The structural analysis demonstrated that the inhibitor HPM could produce more hydrophobic interaction contacts with Aurora A than that of 2JZ, and the loss of key hydrogen bonds between the inhibitor and residue Arg137 in the hinge region of Aurora A was another important reason for the weaker binding affinity of 2JZ to Aurora A. This study sheds more light on the development of the efficient inhibitors targeting the Aurora A.