TY - JOUR
T1 - In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy
AU - Santini, Brianda L.
AU - Zúñiga-Bustos, Matías
AU - Vidal-Limon, Abraham
AU - Alderete, Joel B.
AU - Águila, Sergio A.
AU - Jiménez, Verónica A.
N1 - Funding Information:
The authors thank Aldo Rodriguez for his technical assistance. The authors are grateful to DGTIC-UNAM for access to the Miztli-Universidad Autonoma de Mexico (UNAM) with LANCAD-UNAM-DGTIC-286 Grant. Also, the authors greatly acknowledge the computing support granted by LANCAD and CONACyT in the Supercomputer Hybrid Cluster “Xiuhcoatl” at the General Coordination of Information and Communications Technologies (CGSTIC) of CINVESTAV. The work conducted at Universidad Andres Bello was funded by FONDECYT Grant 1160060. B.L.S. was supported by the Programa de Posgrado en Nanociencias at CICESE-UNAM and by CONACyT. A.V.-L. is the recipient of a DGAPA-UNAM fellowship
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074652119&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.9b00756
DO - 10.1021/acs.jcim.9b00756
M3 - Article
AN - SCOPUS:85074652119
SN - 1549-9596
VL - 60
SP - 786
EP - 793
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 2
ER -
