Modelling Ligand-Quadruplex Interactions

Several studies have shown that structural information derived from the modelling of quadruplex-ligand interactions can lead to new and more effective 

Structural model of the complex of the 3,6,9-trisubstituted acridine ligand (3) with the intramolecular basket quadruplex structure of the human telomeric sequence, (a) End-stacking with the terminal G-tetradpermits the substituent at the 9-position to interact with the flexible TTA loop structure in a specific manner, (b) X-ray structure of the complex of a di-substituted aninoalkylamido acridine (4) with the dimeric hairpin quadruplex structure derived from the Oxytricha nova sequence d(GGGGTTTTGGGG)2. The drug end-stacks and interacts extensively with the thymine loop ((a) Adapted from ref 25 and (b) from RCSB Protein Data Bank co-ordinates ILIH (ref 49)). 

Extending this approach to the design of 3,6,9-trisubstituted acridine ligands 

5 Structure and Dynamics of a Quino-Acridinium Cation Bound to a G-Quadruplex 

6 High-Resolution X-Ray Analysis of Drug-Quadruplex Interactions 

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Shafer, RH (1998) Stability and structure of model DNA triplexes and quadruplexes and their interactions with small ligands. Prog. Nucleic Acid Bes. Mol. Biol. 59, 55-94. 

The oxazole-based click compound 107 was proposed as a G quadruplex ligand. It was particularly selective for those telomeric sequences that form multiple quadruplex motifs. MD simulations suggested a structural model in which the ligand is sandwiched between tandem quadruplexes and involved in several intermolecular interactions (14CC15202). 

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