Structural Basis of Fullerene Derivatives as Novel Potent Inhibitors of Protein Tyrosine Phosphatase 1B: Insight into the Inhibitory Mechanism through Molecular Modeling Studies.

Protein tyrosine phosphatase 1B (PTP1B) has become an outstanding target for the treatment of diabetes and obesity. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of PTP1B, but the specific mechanism remains unclear. Several molecular modeling methods (molecular docking, molecular dynamics simulations, and molecular mechanics/generalized Born surface area calculations) were integrated to provide insight into the binding mode and inhibitory mechanism of the new class of fullerene inhibitors. The results reveal that PTP1B with an open WPD loop is more susceptible to the combination with the fullerene inhibitor because of their comparable shapes and sizes. When the WPD loop fluctuates to the open conformation, the inhibitor falls into the active pocket and induces conformational rotation of the WPD loop. This rotation is closely related to the reduction of the catalytic activity of PTP1B. In addition, it is suggested that compound 1, like compound 2, is a competitive inhibitor since it blocks the active site to prevent the binding of the substrate. The high binding affinity of fullerene-based compounds and the transition of the WPD loop, caused by the specific structural property of the hydrophobic fullerene core and the appended polar groups, make these fullerene derivatives efficient competitive inhibitors. The theoretical results provide useful clues for further investigation of the noval inhibitors of PTP1B at the nanoscale.