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J Environ Sci (China). 2018 Jan;63:285-295. doi: 10.1016/j.jes.2017.08.013. Epub 2017 Aug 30.

Inhibition of thrombin by functionalized C60 nanoparticles revealed via in vitro assays and in silico studies.

Author information

1
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100190, China. Electronic address: liuyanyanhx@163.com.
2
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100190, China.
3
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100190, China; Institute of Environment and Health, Jianghan University, Wuhan 430056, China. Electronic address: aqzhang@rcees.ac.cn.

Abstract

The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C60 NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C60 NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C60 NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C60 NPs, of greater hydrophobicity and hydrogen bond (HB) donor acidity or acceptor basicity, acted as competitive inhibitors of thrombin by directly interacting with the active site of thrombin. A simple quantitative nanostructure-activity relationship model relating the surface substituent properties to the inhibition potential was then established for the six competitive inhibitors. Molecular docking analysis revealed that the intermolecular HB interactions were important for the specific binding of C60 NPs to the active site canyon, while the additional stability provided by the surface groups through van der Waals interaction also play a key role in the thrombin binding affinity of the NPs. Our results suggest that thrombin is a possible target of the surface-functionalized C60 NPs relevant to their anticoagulation effect.

KEYWORDS:

Activity inhibition; C(60) nanoparticle (NP); Molecular docking; Quantitative nanostructure-activity relationship; Surface modification; Thrombin

PMID:
29406112
DOI:
10.1016/j.jes.2017.08.013
[Indexed for MEDLINE]

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