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.蛋白激酶抑制剂（Protein kinase inhibitors）可靶向阻断靶激酶的磷酸化过程，是一类用于治疗癌症及其他疾病的重要药物。传统的基于结构的药物设计方法（如分子对接（molecular docking））多聚焦于激酶抑制剂与其靶点的静态结合模式。然而近年来研究表明，药物分子的解离动力学特性与其体内驻留时间密切相关，该特性因此逐渐受到药物研发人员的关注。本研究借助GROMACS软件所支持的局域缩放分子动力学（local-scaled molecular dynamics, MD）模拟方法，对共计41种I型与II型激酶抑制剂的解离机制展开了系统探究。本次模拟兼顾了多种初始构型以及激酶抑制剂可能存在的质子化状态。基于局域缩放MD模拟结果，本研究发现：在全部数据集范围内，解离过程中有利结合能的积分值与这些激酶抑制剂的实验解离速率常数呈现出良好的相关性（决定系数R²=0.64）。鉴于该方法具备较高精度与技术优势，其有望成为实际研究中估算该关键特性的实用方案。本次模拟还对激酶及其抑制剂的动态特性，以及相关水分子在解离过程中所发挥的作用给出了合理的理论解释。