Abstract

Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinases (MMPs) play a crucial role in cancer proliferation and migration by virtue of their proteolytic functions in angiogenesis and extracelluar matrix (ECM) degradation, making them potential targets of anti-metastaic therapeutics. Recently we showed with both in vivo and in vitro experiments that metallofullerenol Gd@C 82 (OH) 22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C 82 (OH) 22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S1â €2 loop. Here, we expand our study toward another gelatinase, MMP-2, using molecular dynamics simulations. Despite the high structural similarity with 64.3% sequence identity, their responses to Gd@C 82 (OH) 22 were quite different. Toward MMP-2, Gd@C 82 (OH) 22 could block either the Zn 2+ -catalylitic site directly or the S1â €2 loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C 82 (OH) 22 on MMP-2, and then its further location of the most favorable binding site(s). These findings not only illustrated how the inhibitory mechanism of Gd@C 82 (OH) 22 is distinguished between the two gelatinase MMPs with atomic details, but also shed light on the de novo design of anti-metastatic nanotherapeutics with enhanced target specificity.