Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations
Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations
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DOI：
10.1021/jacs.6b12950
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发表时间：
2017-04-05
影响因子：
15
通讯作者：
Parrinello, Michele
中科院分区：
文献类型：
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作者：
Casasnovas, Rodrigo;Limongelli, Vittorio;Parrinello, Michele
了解配体与分子靶标结合的结构和能量要求对药物设计具有至关重要的意义。近年来，原子自由能计算已被证明是一种有效的工具，以补充实验表征的蛋白质/配体相互作用的热力学和动力学性质。在这里，我们通过最近开发的基于元动力学的方案，研究了药理学相关靶标p38 MAP激酶抑制剂的解结合机制。我们提供了配体解结合途径的全面描述，确定了最稳定的结合模式和其他热力学相关的姿势。从我们的模拟中，我们估计解绑定速率为k(off) = 0.020 +/- 0.011 s（-1）。这与实验值(k（off) = 0.14 s(-1)）吻合良好。接下来，我们开发了一个马尔可夫状态模型，该模型允许识别配体解结合过程的限速步骤。我们的计算进一步表明，配体的溶剂化和活性位点的溶剂化在解结合过程中起着至关重要的作用。本研究为研究更复杂的p38抑制剂和其他一般药理学相关抑制剂的解结合动力学铺平了道路，表明元动力学可以成为设计具有工程结合/解结合动力学的新药的有力工具。
Understanding the structural and energetic requisites of ligand binding toward its molecular target is of paramount relevance in drug design. In recent years, atomistic free energy calculations have proven to be a valid tool to complement experiments in characterizing the thermodynamic and kinetic properties of protein/ligand interaction. Here, we investigate, through a recently developed metadynamics-based protocol, the unbinding mechanism of an inhibitor of the pharmacologically relevant target p38 MAP kinase. We provide a thorough description of the ligand unbinding pathway identifying the most stable binding mode and other thermodynamically relevant poses. From our simulations, we estimated the unbinding rate as k(off) = 0.020 +/- 0.011 s(-1). This is in good agreement with the experimental value (k(off) = 0.14 s(-1)). Next, we developed a Markov state model that allowed identifying the rate-limiting step of the ligand unbinding process. Our calculations further show that the solvation of the ligand and that of the active site play crucial roles in the unbinding process. This study paves the way to investigations on the unbinding dynamics of more complex p38 inhibitors and other pharmacologically relevant inhibitors in general, demonstrating that metadynamics can be a powerful tool in designing new drugs with engineered binding/unbinding kinetics.