4.7 Article

Profiling the interaction of a novel toxic pyruvate dehydrogenase kinase inhibitor with human serum albumin

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.saa.2021.119733

Keywords

Human serum albumin; Molecular docking; Spectroscopic assay; Toxicity

Categories

Funding

  1. National Natural Science Foundation of China [21804029, 21807008, 21964018]
  2. distinguished Young Talents of Youjiang Medical University for Nationalities
  3. Natural Science Foundation of Guangxi Province [2018GXNSFAA138211]
  4. Research Program of Baise Science and Technology Development Plan [20201739]
  5. subject academic team of Youjiang Medical University for Nationalities

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available