Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures

Garner, T. P., Williams, H. E., Gluszyk, K. I., Roe, S., Oldham, N. J., Stevens, M. F., Moses, J. E., Searle, M. S. (October 2009) Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures. Org Biomol Chem, 7 (20). pp. 4194-200. ISSN 1477-0520

DOI: 10.1039/b910505k


We report CD, ESI-MS and molecular modelling studies of ligand binding interactions with DNA quadruplex structures derived from the human telomeric repeat sequence (h-Tel) and the proto-oncogenic c-kit promoter sequence. These sequences form anti-parallel (both 2 + 2 and 3 + 1) and parallel conformations, respectively, and demonstrate distinctively different degrees of structural plasticity in binding ligands. With h-Tel, we show that an extended heteroaromatic 1,4-triazole (TRZ), designed to exploit pi-stacking interactions and groove-specific contacts, shows some selectivity for parallel folds, however, the polycyclic fluorinated acridinium cation (RHPS4), which is a similarly potent telomerase inhibitor, shows selectivity for anti-parallel conformations implicating favourable interactions with lateral and diagonal loops. In contrast, the unique c-kit parallel-stranded quadruplex shows none of the structural plasticity of h-Tel with either ligand. We show by quantitative ESI-MS analysis that both sequences are able to bind a ligand on either end of the quadruplex. In the case of h-Tel the two sites have similar affinities, however, in the case of the c-kit quadruplex the affinities of the two sites are different and ligand-dependent. We demonstrate that two different small molecule architectures result in significant differences in selectivity for parallel and anti-parallel quadruplex structures that may guide quadruplex targeted drug-design.

Item Type: Paper
Uncontrolled Keywords: Acridines/*chemistry/*pharmacology Circular Dichroism DNA/*chemistry/metabolism Enzyme Inhibitors/chemistry/pharmacology G-Quadruplexes/*drug effects Humans Ligands Mass Spectrometry Molecular Dynamics Simulation Proto-Oncogene Proteins c-kit/genetics Substrate Specificity Telomerase/antagonists & inhibitors Telomere/genetics Triazoles/*chemistry/*pharmacology
CSHL Authors:
Communities: CSHL labs > Moses lab
Depositing User: Matthew Dunn
Date: 21 October 2009
Date Deposited: 19 Apr 2021 20:07
Last Modified: 19 Apr 2021 20:07
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