Profiling the interaction of a novel toxic pyruvate dehydrogenase kinase inhibitor with human serum albumin
Profiling the interaction of a novel toxic pyruvate dehydrogenase kinase inhibitor with human serum albumin
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分析新型有毒丙酮酸脱氢酶激酶抑制剂与人血清白蛋白的相互作用
DOI：
10.1016/j.saa.2021.119733
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Shen Yizhong
中科院分区：
文献类型：
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作者：
Liao Xianjiu;Zhu Chunlei;Huang Ding;Wen Xiaoqing;Zhang Shao-Lin;Shen Yizhong
为了寻找新的丙酮酸脱氢酶激酶（PDK）抑制剂，鉴定了一种新的化合物2,2-二氯-1-（4-（4-异丙基苯基）氨基）-3-硝基苯基)e比-1- 1，即xb -1，该化合物抑制PDK活性的一半最大抑制浓度（IC50）值为337.0 nM，抑制A549细胞增殖的一半最大有效浓度（EC50）值为330.0 nM。然而，该化合物似乎在癌细胞和正常细胞之间表现出可忽略不计的选择性，表明该化合物存在潜在的毒性。本文首先通过光谱方法探讨了毒物xb -1与人血清白蛋白（HSA）的相互作用，目的是在下一次hit-to-lead活动中减少/避免PDK抑制剂的毒性。在PBS缓冲液（pH = 7.4, 10.0 mM）中，xb -1主要通过氢键相互作用与HSA有效结合，形成HSA- xb -1配合物。ΔGshowed的负值表明xb -1与HSA的结合是一个自发的过程。位点选择性结合实验结果表明，xb -1与华法林竞争结合到HSA的I位点，与分子对接方法完全一致。本文的研究结果可为研究生物功能分子的毒性提供有价值的理论基础，并为如何避免/减少小分子的毒性提供思路。
To discover novel pyruvate dehydrogenase kinase (PDK) inhibitors, a new compound 2,2-dichloro-1-(4-((4-isopropylphenyl)amino)-3-nitrophenyl)ethan-1-one, namelyXB-1was identified, which inhibited PDK activity with a half maximal inhibitory concentration (IC50) value of 337.0 nM, and reduced A549 cell proliferation with a half maximal effective concentration (EC50) value of 330.0 nM. However, the compound appears to exhibit a negligible selectivity between cancer cell and normal one, indicating a potential toxicity existed for the compound. Herein, the interaction of the toxicXB-1to human serum albumin (HSA) was firstly explored by spectroscopic approaches with the aim to reduce/avoid the toxicity of PDK inhibitors in the next hit-to-lead campaign. In detail, it was found that theXB-1could effectively bind to HSA mainlyviahydrogen bond interaction in PBS buffer (pH = 7.4, 10.0 mM), resulting in the formation of HSA-XB-1complex. The negative value of ΔGshowed that the binding ofXB-1to HSA is a spontaneous process. The result from site-selective binding assay suggested that theXB-1bound to the site I of HSA by competing with warfarin, which was perfect in agreement with the molecular docking method. The results of this paper may offer a valuable theoretical basis to study the toxicity of biofunctional molecules and may offer thoughts about how to avoid/reduce toxicity for a small molecule.