Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Molecular Insights into the Specific Targeting of c-MYC G-quadruplex by Cell-Penetrating Peptides: An in silico Study

Sen Cao
,
Qian Su
,
Yonghao Chen
,
Menglu Wang
,
Yi Xu
,
Lihui Wang
ORCID logo ,
Yanhua Lu
,
Jianfeng Li
,
Jun Liu
ORCID logo ,
Xiaojing Hong
,
Hongyan Wang
,
Jun-Ping Liu
* ,
Zhiguo Wang
* ORCID logo
Version 1 : Received: 12 December 2023 / Approved: 12 December 2023 / Online: 13 December 2023 (10:55:36 CET)

A peer-reviewed article of this Preprint also exists.

Cao, S.; Su, Q.; Chen, Y.-H.; Wang, M.-L.; Xu, Y.; Wang, L.-H.; Lu, Y.-H.; Li, J.-F.; Liu, J.; Hong, X.-J.; Wang, H.-Y.; Liu, J.-P.; Wang, Z.-G. Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides. Int. J. Mol. Sci. 2024, 25, 623. Cao, S.; Su, Q.; Chen, Y.-H.; Wang, M.-L.; Xu, Y.; Wang, L.-H.; Lu, Y.-H.; Li, J.-F.; Liu, J.; Hong, X.-J.; Wang, H.-Y.; Liu, J.-P.; Wang, Z.-G. Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides. Int. J. Mol. Sci. 2024, 25, 623.

Abstract

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for the c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards the c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Keywords

oncogene promotor; c-MYC; G-quadruplex; thiazole peptide; molecular docking; molecular dynamics; MM/GBSA

Subject

Biology and Life Sciences, Biophysics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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