Contrasting Effects of Inhibitors Li + and Be 2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β
Contrasting Effects of Inhibitors Li + and Be 2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β
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抑制剂 Li 和 Be 2 对糖原合成酶激酶-3β 催化循环的对比作用
DOI：
10.1021/acs.jpcb.1c05099
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Alexandrova, Anastassia N.
中科院分区：
文献类型：
--
作者：
Reilley, David J.;Arraf, Zaher;Alexandrova, Anastassia N.
锂离子显示出罕见的治疗双相情感障碍的有效性，是一种潜在的神经退行性疾病的药物。不幸的是，锂具有显著的缺点，主要是狭窄的治疗窗口。在锂的作用靶点中，糖原合成酶激酶3β（GSK-3β）可能是锂发挥治疗作用的重要靶点。开发这种激酶的替代性选择性抑制剂可以防止锂的副作用，但迄今为止，这些努力几乎没有取得成功。因此，对Li+抑制和GSK-3β磷酸化反应的原子理解将有助于新药的开发。在这项研究中，我们使用我们的混合量子-经典动力学方法QM/DMD和竞争性金属亲和力（CMA）方法的结合亲和力的催化状态的广泛采样扩展Li+GSK-3β抑制的原子图像。我们比较Li+的行动与Be 2+，并发现我们的结果在一致的vitrokinetics研究。最终，我们的模拟表明，Li+抑制是通过降低磷酸化反应速率来驱动的，而不是通过与不同GSK-3β状态的紧密结合来降低催化转换，如Be 2+抑制。这些金属的作用源于静电差异，特别是与天然Mg 2+相比其更小的原子半径，因此为基于其他范例的GSK-3β抑制剂的开发提供了见解。
Ionic lithium shows rare effectiveness for treating bipolar disorder and is a potential drug for neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks, mainly a narrow therapeutic window. Among the targets of lithium, glycogen synthase kinase 3β (GSK-3β) may be responsible for its therapeutic effects. The development of alternative, selective inhibitors of this kinase could prevent lithium side effects, but such efforts have met little success so far. An atomistic understanding of Li+inhibition and the GSK-3β phosphorylation reaction would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to expand the atomistic picture of Li+GSK-3β inhibition. We compare Li+action with Be2+and find our results in agreement within vitrokinetics studies. Ultimately, our simulations show that Li+inhibition is driven by decreasing the phosphorylation reaction rate, rather than reducing catalytic turnover through tight binding to different GSK-3β states like Be2+inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg2+and thus provide insight for the development of GSK-3β inhibitors based on other paradigms.