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Ligand Induced Conformational Preorganization of Loops of c-MYC G-Quadruplex DNA and its Implications in Structure Specific Drug Design

Abstract

Stabilization of G-quadruplex (G4) DNA structure in the proto-oncogene c-MYC utilizing small molecule ligands has emerged as an attractive strategy to develop anticancer therapeutics. To understand the subtle structural changes in the G4 structure upon ligand binding, molecular dynamics (MD) simulations of c-MYC G4 DNA was carried out in complex with six different potent ligands: 3AQN, 6AQN, 3APN, 360A, Nap-Et and Nap-Pr. 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. The two-dimensional dynamic correlation maps unraveled the ligand-induced correlated motions between guanines in the quartet and a di-nucleotide present in the propeller loop-2 of the G4 structure. Cluster analysis and ONIOM calculations reveal 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.

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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, Accepted Manuscript
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    Ligand Induced Conformational Preorganization of Loops of c-MYC G-Quadruplex DNA and its Implications in Structure Specific Drug Design

    H. S, S. Kotaru and P. I. Pradeepkumar, Mol. BioSyst., 2017, Accepted Manuscript , DOI: 10.1039/C7MB00175D

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