期刊
MOLECULAR PHARMACEUTICS
卷 15, 期 12, 页码 5637-5645出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b00806
关键词
dabrafenib; human serum albumin; esterase-like activity; antioxidant activity; molecular dynamics simulation
资金
- National Natural Science Foundation of China [21808020]
- Applied Basic Research Project of Sichuan Province [2018JY0151]
- Sichuan Science and Technology Program [2018JY0188]
- Fundamental Research Funds for the Central Universities [2018SCU12043]
Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using F-19 NMR, spectroscopy methods, and molecular dynamics simulation. The results of F-19 NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib.
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