In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy.
J Chem Inf Model
; 60(2): 786-793, 2020 02 24.
Article
in En
| MEDLINE
| ID: mdl-31657548
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Computer Simulation
/
Mucin-1
/
Aptamers, Nucleotide
/
Molecular Targeted Therapy
/
Neoplasms
Language:
En
Journal:
J Chem Inf Model
Journal subject:
INFORMATICA MEDICA
/
QUIMICA
Year:
2020
Document type:
Article