Nanoparticles play many important roles in nanomedicine from diagnostics to therapeutics. In this study, we investigated the potential of Gd@C82(OH)22 as a tumor chemotherapeutic agent against matrix metalloproteinase-9 (MMP-9), a zinc-dependent endoprotease that breaks down extracellular matrix proteins and is associated with tumor metastasis. Unlike most MMP inhibitors, which target the conserved catalytic zinc site, Gd@C82(OH)22 indirectly inhibits MMP-9 activity by allosteric binding at the ligand specificity S1’ loop. However, the binding is limited as Gd@C82(OH)22 tends to self-aggregate in aqueous solutions. To enhance binding affinity of Gd@C82(OH)22 for the S1’ loop, we designed Gd@C82(OH)22 derivatives by substituting a small, biocompatible, charged or polar functional group (–PO42-, –CH2CO2-, –CO2-, –NH3+, or –CONH2) for a hydroxyl group on the Gd@C82(OH)22 surface. Then we calculated the change in the binding free energy to the catalytic domain of human MMP-9 using the Free Energy Perturbation method. We found that the higher the net charge of the functional group, the stronger the binding. Compared with Gd@C82(OH)22, Gd@C82(OH)21(PO4)2- binds at least 1.5 to 2.5 kcal/mol more strongly to MMP-9 due to favorable electrostatic interactions between the phosphate group and the positively-charged residues at the binding site. In addition to the net charge, the binding free energy can be delicately adjusted by other factors, such as the position of mutation on the Gd@C82(OH)22 surface, the local environment of the charged residues of MMP-9 which interact with the functional groups, and the presence of ions near the charged functional group. Taken all together, the results of our study provide new insights to the development of Gd@C82(OH)22 derivatives as nanodrugs for treating the pathological diseases associated with unregulated MMP-9 activity.

Increasing binding affinity of Gd@C82(OH)22 for human MMP-9 by mutation of a surface functional group

256th National Meeting (2018)

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