Journal
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
Volume 256, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.saa.2021.119733
Keywords
Human serum albumin; Molecular docking; Spectroscopic assay; Toxicity
Categories
Funding
- National Natural Science Foundation of China [21804029, 21807008, 21964018]
- distinguished Young Talents of Youjiang Medical University for Nationalities
- Natural Science Foundation of Guangxi Province [2018GXNSFAA138211]
- Research Program of Baise Science and Technology Development Plan [20201739]
- subject academic team of Youjiang Medical University for Nationalities
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The newly discovered PDK inhibitor XB-1 showed potent inhibitory effects on cancer cells but lacked selectivity, suggesting potential toxicity.
To discover novel pyruvate dehydrogenase kinase (PDK) inhibitors, a new compound 2,2-dichloro-1-(4((4-isopropylphenyl)amino)-3-nitrophenyl)ethan-1-one, namely XB-1 was 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 toxic XB-1 to 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 the XB-1 could effectively bind to HSA mainly via hydrogen bond interaction in PBS buffer (pH = 7.4, 10.0 mM), resulting in the formation of HSA-XB-1 complex. The negative value of DG showed that the binding of XB-1 to HSA is a spontaneous process. The result from site-selective binding assay suggested that the XB-1 bound 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. (c) 2021 Elsevier B.V. All rights reserved.
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