Abstract

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 (IC 50 ) value of 337.0 nM, and reduced A549 cell proliferation with a half maximal effective concentration (EC 50 ) 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 Δ G 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.