Revealing the Unbinding Kinetics and Mechanism of Type I and Type II Protein Kinase Inhibitors by Local-Scaled Molecular Dynamics Simulations.

Protein kinase inhibitors disrupt phosphorylation of the target kinases, which are an important class of drug for treating cancer and other diseases. Conventional structure-based design methods (such as molecular docking) focus on the static binding mode of the kinase inhibitor with its target. However, dissociation kinetic properties of a drug molecule are found to correlate with its residence time in vivo and thus have drawn the attention of drug designers in recent years. In this study, we have applied the local-scaled molecular dynamics (MD) simulation enabled in GROMACS software to explore the unbinding mechanism of a total of 41 type I and type II kinase inhibitors. Our simulation considered multiple starting configurations as well as possible protonation states of kinase inhibitors. Based on our local-scaled MD results, we discovered that the integrals of the favorable binding energy during dissociation correlated well (R2 = 0.64) with the experimental dissociation rate constants of those kinase inhibitors on the entire data set. Given its accuracy and technical advantage, this method may serve as a practical option for estimating this important property in reality. Our simulation also provided a reasonable explanation of the dynamic properties of kinase and its inhibitor as well as the role of relevant water molecules in dissociation.