Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore.
Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore.
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DOI：
10.1007/s10822-016-9922-3
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发表时间：
2016-06
影响因子：
3.5
通讯作者：
Hassan, S. A.
中科院分区：
文献类型：
--
作者：
Cardone, A.;Brady, M.;Sriram, R.;Pant, H. C.;Hassan, S. A.
关键词：
由激活蛋白 p25 诱导的循环依赖性激酶 5 (CDK5) 的过度活跃与许多大脑病理学相关。因此，CDK5-p25 复合物已成为阿尔茨海默病 (AD) 和其他神经退行性疾病的主要治疗靶点。实验表明，肽p5可降低CDK5-p25活性，而不影响内源性CDK5-p35活性，而从p5获得的肽TFP5可引起类似的抑制作用，穿过血脑屏障，对AD小鼠模型表现出行为拯救作用，且无毒副作用。激酶抑制的分子基础目前尚不清楚，这里通过计算机模拟进行研究。结果表明，p5 在相同的 CDK5/p25 和 CDK5/p35 界面结合激酶，因此是两种激活剂的非选择性竞争者，与现有的体外实验数据一致。 p5 的结合是由焓驱动的，亲和力估计在低 μM 范围内。给出了结合位点和药效团的定量描述，并讨论了在类药化合物设计中提高结合亲和力和选择性的选项。
The hyperactivity of the cyclic dependent kinase 5 (CDK5) induced by the activator protein p25 has been linked to a number of pathologies of the brain. The CDK5-p25 complex has thus emerged as a major therapeutic target for Alzheimer’s disease (AD) and other neurodegenerative conditions. Experiments have shown that the peptide p5 reduces the CDK5-p25 activity without affecting the endogenous CDK5-p35 activity, whereas the peptide TFP5, obtained from p5, elicits similar inhibition, crosses the blood-brain barrier, and exhibits behavioral rescue of AD mice models with no toxic side effects. The molecular basis of the kinase inhibition is not currently known, and is here investigated by computer simulations. It is shown that p5 binds the kinase at the same CDK5/p25 and CDK5/p35 interfaces, and is thus a non-selective competitor of both activators, in agreement with available experimental data in vitro. Binding of p5 is enthalpically driven with an affinity estimated in the low μM range. A quantitative description of the binding site and pharmacophore is presented, and options are discussed to increase the binding affinity and selectivity in the design of drug-like compounds.
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影响因子：
3
作者：
Cardone, Antonio;Bornstein, Aaron;Pant, Harish C.;Brady, Mary;Sriram, Ram;Hassan, Sergio A.
通讯作者：
Hassan, Sergio A.
DOI：
10.1016/b978-0-12-374920-8.00916-4
发表时间：
2011-01-01
期刊：
COMPREHENSIVE BIOPHYSICS, VOL 9: SIMULATION AND MODELLING
影响因子：
--
作者：
Hassan, S. A.;Mehler, E. L.
通讯作者：
Mehler, E. L.
影响因子：
4.8
作者：
Knockaert, M;Wieking, K;Meijer, L
通讯作者：
Meijer, L
影响因子：
4.4
作者：
Andricioaei, I;Karplus, M
通讯作者：
Karplus, M
影响因子：
1.7
作者：
Cardone, Antonio;Albers, R. Wayne;Pant, Harish C.
通讯作者：
Pant, Harish C.