Fullerene derivatives act as inhibitors of leukocyte common antigen based on molecular dynamics simulations

Fullerene-based molecules are being studied as potential inhibitors of protein tyrosine phosphatases due to their unique properties and low toxicity. However, the underlying molecular mechanism remains elusive. In this study, molecular dynamics (MD) simulations in conjunction with molecular docking calculations were utilized to investigate the binding effects of C-60, C-60(NH2)(30), and C-60(OH)(30) on the enzymatic activity of CD45 (a receptor-like protein tyrosine phosphatase). Our results show that all the investigated molecules can be docked into the region between D1 and D2 domains of CD45, and stabilize the protein structure. The average number of residues that directly interact with the C-60(NH2)(30) is two more than that of C-60(OH)(30), F819 and F820 (located in the loop connects 3 and 12), resulting in different effects of C-60(NH2)(30) and C-60(OH)(30) on protein activity. Detailed MD simulation analyses show that transformation of the interaction network caused by C-60(NH2)(30) is completely different from that of the control simulation due to the misfolding of 3. Furthermore, the movement of D1 active pocket and KNRY motif are most severely impaired by docking with C-60(NH2)(30). Our simulation results illustrate that fullerene derivatives modified with amino groups exhibit conspicuous tumor inhibition to protein tyrosine phosphatases, and can act as effective inhibitors. Our results give insight into the inhibitory effects of fullerene-based molecules on protein tyrosine phosphatases and providing a theoretical basis for the design of effective inhibitors.