Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions.
Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions.
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DOI：
10.1038/srep12157
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发表时间：
2015-07-16
影响因子：
4.6
通讯作者：
Lian LY
中科院分区：
文献类型：
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作者：
Bach A;Pedersen SW;Dorr LA;Vallon G;Ripoche I;Ducki S;Lian LY
ZL006和IC87201被认为是nNOS/PSD-95蛋白-蛋白相互作用的有效抑制剂，在缺血性卒中和疼痛的细胞实验和动物模型中显示出很大的前景。本文采用荧光极化（FP）、等温滴定量热法（ITC）和1H-15N HSQC NMR等生化和生物物理方法研究了ZL006和IC87201的作用机制。我们的数据表明，在体外应用条件下，ZL006和IC87201不与nNOS或PSD-95的PDZ结构域相互作用，也不通过与nNOS-PDZ的β指相互作用来抑制nNOS-PDZ/PSD-95-PDZ界面。本研究结果对ZL006、IC87201及其类似物的进一步药物化学研究具有指导意义，并对其作用机制的普遍观点提出了挑战。
ZL006 and IC87201 have been presented as efficient inhibitors of the nNOS/PSD-95 protein-protein interaction and shown great promise in cellular experiments and animal models of ischemic stroke and pain. Here, we investigate the proposed mechanism of action of ZL006 and IC87201 using biochemical and biophysical methods, such as fluorescence polarization (FP), isothermal titration calorimetry (ITC), and 1H-15N HSQC NMR. Our data show that under the applied in vitro conditions, ZL006 and IC87201 do not interact with the PDZ domains of nNOS or PSD-95, nor inhibit the nNOS-PDZ/PSD-95-PDZ interface by interacting with the β-finger of nNOS-PDZ. Our findings have implications for further medicinal chemistry efforts of ZL006, IC87201 and analogues, and challenge the general and widespread view on their mechanism of action.