Inhibition of thrombin by functionalized C_（60） nanoparticles revealed via in vitro assays and in silico studies

• Published in: Journal of environmental sciences (China) 2018, Vol.63 (1), p.285-295
• Main Authors: Liu, Yanyan, Fu, Jianjie, Pan, Wenxiao, Xue, Qiao, Liu, Xian, Zhang, Aiqian
• Format: Article
• Language: English
• Subjects: Computer Simulation; Fullerenes - chemistry; Fullerenes - toxicity; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Kinetics; Models, Chemical; Molecular Docking Simulation; Surface Properties; Thrombin - metabolism; 酵素; 凝血; 表面化学性质; Fullerene; fullerene; 金; 相互作用; 竞争力
• ISSN: 1001-0742; 1878-7320
• DOI: 10.1016/j.jes.2017.08.013

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（C_（60） 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 C_（60） NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C_（60） NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C_（60） 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 C_（60） 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 C_（60） NPs relevant to their anticoagulation effect.