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Title: Crystallographic and molecular modelling studies of G-quadruplex-ligand complexes
Author: Campbell, Nancy Husni
ISNI:       0000 0004 2687 243X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2010
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The majority of cancer cells are innately proficient at maintaining the length of telomeric DNA sequence present at the ends of their linear chromosomes. Telomerase, in its capping and illegitimate activation of its catalytic function, is central to this. Small molecules may interact with telomeric DNA sequences, inducing and/or stabilising the formation of four-stranded DNA quadruplex structures, which thus inhibit telomerase. Detailed structural description of G-quadruplexes in their native and complex forms, enables the application of rational drug design approaches by developing small molecules that have high specificity for their unique structural features. This may lead to selective and differential targeting of the various forms of G-quadruplexes. The work in this thesis describes the detailed molecular structures of several quadruplex-small molecule complexes, of relevance to rational drug design. The crystal structure is reported of a complex between the bimolecular human telomeric quadruplex formed by the sequence d[TAGGGTTAGGGT]2 and the experimental anticancer drug BRACO19, to a resolution of 2.5 Å. This has revealed an intricate binding site, whereby BRACO19 is sandwiched between two consecutively-stacked parallel-stranded quadruplexes at the dimeric 5' - 3' interface: stacking onto a G-tetrad at the 3' face and a TATA-tetrad at the 5' face. The co-crystal structures of the Oxytricha nova telomeric sequence d[GGGGTTTTGGGG]2 in complex with a series of six 3,6-disubstituted aminoalkylamido acridine compounds are reported. All the structures are homologous with a published crystal structure in complex with a closely related ligand whereby the ligands are stacking between a G-tetrad and a diagonal T4 loop albeit revealing a unique adaptation in the position of the 3- and 6- cyclic-amine end groups affected by their size and ortho/para substitutions. Computational methods have been used, comprising molecular dynamics simulations and free energy calculations, enabling in silico comparison of ligand-quadruplex interactions where crystallisation experiments have not been attempted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available