Simulation of ligand dissociation kinetics from the protein kinase PYK2.
Simulation of ligand dissociation kinetics from the protein kinase PYK2.
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从蛋白激酶Pyk2中的配体解离动力学的模拟。
DOI：
10.1002/jcc.26991
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发表时间：
2022-10-30
影响因子：
3
通讯作者：
Wong CF
中科院分区：
文献类型：
--
作者：
Spiriti J;Noé F;Wong CF
早期的药物发现项目通常集中在与靶点的平衡结合亲和力以及选择性和其他药物特性。药物结合的动力学被忽视，但可能对药物功效产生显着影响。因此，在药物发现过程的早期评估药物结合动力学已经受到越来越多的关注。在原子水平上模拟药物结合动力学对于所涉及的长时间尺度是具有挑战性的。在这里，我们使用了基于转换的重新加权分析方法（TRAM）与马尔可夫状态模型，研究从蛋白激酶PYK2的配体的解离。TRAM结合了有偏和无偏模拟，以减少计算成本。这项工作使用了雨伞抽样技术的偏见模拟。虽然使用过渡态理论的伞式采样模拟的平均力的潜力高估了三个数量级的解离速率，但TRAM给出的解离速率在实验值的一个数量级内。本页面的内容将仅作为html图形摘要的一部分。它不会作为main的一部分发布。使用基于跃迁的再加权分析方法（TRAM），我们表明抑制剂从PYK2蛋白激酶的结合态（4）解离在完全解离之前经历中间态（2）到两个预解离态（0和3）。我们还发现了一个错误捕获的束缚态（1），它以比真正束缚态更高的能量与PYK 2结合。该模型预测的解离速率在一个数量级的实验。
Early-stage drug discovery projects often focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. The kinetics of drug binding are ignored but can have significant influence on drug efficacy. Therefore, increasing attention has been paid on evaluating drug-binding kinetics early in a drug discovery process. Simulating drug-binding kinetics at the atomic level is challenging for the long time scale involved. Here, we used the transition-based reweighting analysis method (TRAM) with the Markov state model to study the dissociation of a ligand from the protein kinase PYK2. TRAM combines biased and unbiased simulations to reduce computational costs. This work used the umbrella sampling technique for the biased simulations. Although using the potential of mean force from umbrella sampling simulations with the transition-state theory over-estimated the dissociation rate by three orders of magnitude, TRAM gave a dissociation rate within an order of magnitude of the experimental value. The contents of this page will be used as part of the graphical abstract of html only. It will not be published as part of main. Using the transition-based reweighing analysis method (TRAM), we showed that the dissociation of an inhibitor from the bound state (4) of the PYK2 protein kinase went through an intermediate state (2) to two pre-dissociated states (0 and 3) before complete dissociation. We also found a mis-trapped bound state (1) that bound to PYK2 with a higher energy than the true bound state. The model predicted a dissociation rate within an order of magnitude of experiment.
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影响因子：
8.6
作者：
Berger, Benedict-Tilman;Amaral, Marta;Knapp, Stefan
通讯作者：
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影响因子：
4.4
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影响因子：
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作者：
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通讯作者：
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作者：
Bolhuis, PG;Dellago, C;Chandler, D
通讯作者：
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