Structural Basis Of Different Surface-Modified Fullerene Derivatives As Novel Thrombin Inhibitors: Insight Into The Inhibitory Mechanism Through Molecular Modelling Studies

Thrombin is the main target of antithrombotic and anticoagulant therapy. Although recent studies have shown that surface-modified fullerene derivatives can be used as novel nano-anticoagulants to effectively inhibit thrombin, the specific mechanism remains unclear. In this study, we investigated the binding mode and inhibition mechanism of fullerenes with thrombin by using various molecular modelling approaches. The results showed that owing to the hydrophobicity of the fullerene skeleton, the four existing fullerene inhibitors mainly combined with the active site of thrombin through van der Waals interaction and tended to make the surrounding environment hydrophobic. This made the inhibitors with hydrophobic side chains, especially those with large hydrophobic side chains containing benzene rings, have greater binding free energy with protein. However, as more hydrophilic groups can change the surrounding hydrophilic-hydrophobic environment and form more hydrogen bonds, the electrostatic contribution of the polyhydroxy side chain designed in this study was increased further. At the same time, the van der Waals interaction between the fullerene carbon skeleton and protein did not decrease significantly, resulting in a significantly increased total binding free energy and an enhanced inhibition effect. These findings provide a theoretical basis for the improvement of highly effective fullerene anticoagulants.