Jump to main content
Jump to site search

Issue 8, 2017
Previous Article Next Article

Ligand-induced conformational preorganization of loops of c-MYC G-quadruplex DNA and its implications in structure-specific drug design

Author affiliations

Abstract

Stabilization of a G-quadruplex (G4) DNA structure in the proto-oncogene c-MYC using small molecule ligands has emerged as an attractive strategy for the development of anticancer therapeutics. To understand the subtle structural changes in the G4 structure upon ligand binding, molecular dynamics (MD) simulations of c-MYC G4 DNA were carried out in a complex with six different potent ligands: 3AQN, 6AQN, 3APN, 360A, Nap-Et, and Nap-Pr. The results show that the ligands 3AQN, 6AQN, 3APN, and 360A stabilize the G4 structure by making stacking interactions with the top quartet. On the other hand, Nap-Et and Nap-Pr bind at the groove of the G4 structure. These groove binding ligands make crucial H-bond contacts with the guanines and electrostatic interactions with the phosphate backbone. Two-dimensional dynamic correlation maps unraveled the ligand-induced correlated motions between the guanines in the quartet and a di-nucleotide present in the propeller loop-2 of the G4 structure. Cluster analysis and ONIOM calculations revealed the structural dynamics in the loop of the quadruplex upon ligand binding. Overall, the results from the present study suggest that engineering specific contacts with the propeller loop can be an efficient way to design c-MYC G4-specific ligands.

Graphical abstract: Ligand-induced conformational preorganization of loops of c-MYC G-quadruplex DNA and its implications in structure-specific drug design

Back to tab navigation

Supplementary files

Publication details

The article was received on 22 Mar 2017, accepted on 02 Jun 2017 and first published on 02 Jun 2017


Article type: Paper
DOI: 10.1039/C7MB00175D
Citation: Mol. BioSyst., 2017,13, 1458-1468
  •   Request permissions

    Ligand-induced conformational preorganization of loops of c-MYC G-quadruplex DNA and its implications in structure-specific drug design

    S. Harikrishna, S. Kotaru and P. I. Pradeepkumar, Mol. BioSyst., 2017, 13, 1458
    DOI: 10.1039/C7MB00175D

Search articles by author

Spotlight

Advertisements