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
Abstract
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 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/39535 |
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