Dual inhibitory pathways of metallofullerenol Gd@C₈₂(OH)₂₂ on matrix metalloproteinase-2: molecular insight into drug-like nanomedicine.
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@C82(OH)22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C82(OH)22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S1' 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@C82(OH)22 were quite different. Toward MMP-2, Gd@C82(OH)22 could block either the Zn(2+)-catalylitic site directly or the S1' loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C82(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@C82(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.
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
Seung-gu
SG
Kang
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
Raul
R
Araya-Secchi
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
Deqiang
D
Wang
Soft Matter Research Center, Zhejiang University, Hangzhou 310027, China.
Bo
B
Wang
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
Tien
T
Huynh
1] Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA [2] Soft Matter Research Center, Zhejiang University, Hangzhou 310027, China [3] Department of Chemistry, Columbia University, New York, NY 10027, USA.
Ruhong
R
Zhou
D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D037741:Fullerenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005682:Gadolinium / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050997:Nanomedicine; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects*
D037741:Fullerenes; D061965:Matrix Metalloproteinase Inhibitors; D005682:Gadolinium; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9