期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 60, 期 2, 页码 786-793出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.9b00756
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类别
资金
- DGTIC-UNAM [LANCAD-UNAM-DGTIC-286]
- FONDECYT [1160060]
- Programa de Posgrado en Nanociencias at CICESE-UNAM
- CONACyT
- DGAPA-UNAM
The transmembrane glycoprotein mucin 1 (MUC1) is an attractive tumor marker for cancer therapy and diagnosis. The nine amino acid extracellular epitope APDTRPAPG of this protein is selectively recognized by the S2.2 single-stranded DNA anti-MUC1 aptamer, which has emerged as a promising template for designing novel targeting agents for MUC1-directed therapy. In this work, 100 ns molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and conformational analysis were employed to propose a novel prospective anti-MUC1 aptamer with increased affinity toward the MUC1 epitope resulting from the double mutation of the T11 and T12 residues with PSU and U nucleosides, respectively. The double mutant aptamer exhibits a tight interaction with the MUC1 epitope and adopts a groove conformation that structurally favors the intermolecular contact with the epitope through the intermediate T11-A18 region leaving the 3' and 5' ends free for further chemical conjugation with a nanocarrier or pharmaceutical. These results are valuable to gain understanding about the molecular features governing aptamer-epitope interactions and constitute a first key step for the design of novel aptamer-based nanocarriers for MUC1-targeted cancer therapy.
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