This thesis involves the use of large scale molecular dynamics simulations and associated analysis techniques to study DNA structure and recognition. LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) is a scalable molecular dynamics code including long-range Coulomb interactions that has been specifically designed to function efficiently on parallel platforms. Here we describe the implementation of the AMBER98 forcefield in LAMMPS and its validation for molecular dynamics investigations of DNA structure and flexibility against benchmark AMBER6 code results. Extended MD simulations on the hydrated DNA dodecamer d(CTITIGCAAAAG)₂ and 1:1 and 2:1 drug complexes, which have previously been the subject of extensive dynamical analysis using AMBER6, show that it is possible to obtain excellent agreement in terms of static, dynamic and thermodynamic parameters between AMBER6 and LAMMPS. Also, compared to AMBER6, LAMMPS shows greatly improved scalability in massively parallel environments (Cray T3E). The telomerase enzyme is active in 85-90% of human tumours and is therefore an important target in anti-cancer drug design. Telomerase acts at the telomeric regions of chromosomes adding successive (TIAGGG)n repeats causing immortalisation of the cell. Telomerase can be inhibited by the stabilisation of G-quadruplexes which, in vitro studies show, are formed in these telomeric regions. In order to minimise non-specific toxicity associated with this approach it is important that the drugs preferentially bind to quadruplex over duplex DNA. A series of novel polycyclic acridine salts have been synthesised within our laboratories that show this property. MD studies have been used to study alternative binding relationships of RHPS4 (our lead compound) to quadruplex and duplex DNA and to explore the differences in binding profiles of RHPS4 and its methyl derivative RHPS3. Analysis of extended simulations (≥3ns) has been carried out including evaluation of ΔG from enthalpic and entropic contributions, linear interaction energy, stacking interactions and molecular interaction potentials. "Correct" binding positions for RHPS4 in quadruplex and duplex DNA have been found and simulations and analysis of RHPS3 also carried out. Although the results are not conclusive and do not all agree with the experimental data we can conclude that quadruplex verses duplex selectivity is governed by a subtle balance between many factors, including electrostatic and vdW interactions, DNA flexibility and most probably the models used.

Chinese herbal remedies (CHRs) are commonly prescribed for the treatment of cancer, however their use is often based on the belief systems of traditional Chinese medicine (TCM), and there is relatively little information regarding their efficacy or biological action. Thus, the aim of this investigation was to select a range of CHRs with some suggestion of tumour modulatory activity, and to devise and implement a strategy with which to investigate their direct toxicity to cancer cells, in an attempt to elucidate their potential efficacy and mode of action. The CHRs ‘OldenIandia diffusa’ (OD), Long Dan Xie Gan Wan (LD), ‘Polygonum multiflorum’ (PM) and ‘Polyporus umbellatus’ (PU) were selected for this investigation, and their direct cytotoxic potential against cancer cells examined using an ‘in vitro’ cell-based system. Initially, water and ethanol extracts of each CHR were made and their toxicity evaluated against a range of cancer cell lines (HL60, HT29, HCT-8, HeLa and CHO). The results of this study suggested that water extracts of OD, LD and PM, but not PU, were significantly toxic to a range of cancer cell types. Further investigation (using the HL60 and HT29 cell lines) suggested that OD and LD induced apoptosis in cancer cell lines ‘in vitro’ through activation of the intrinsic pro-apoptotic signalling pathway (characterised by activation of caspase 9), possibly through the induction of genotoxic damage, and that this activity was related to the combined actions of a number of cytotoxic compounds, and not to a single constituent. Furthermore, OD and LD were found to be less toxic to cultured primary blood lymphocytes (PBLs), thus further suggesting that there may be some scientific basis for their use in the treatment of cancer. Further investigation into the cytotoxic action of water extracts of PM revealed that it was inducing necrosis in cancer cell lines and not apoptosis, thus suggesting that PM does not possess anticancer activity. Overall, the results of this investigation suggest that OD and LD may be a source of novel chemotherapeutic agents, and that there may be some scientific basis for their traditional use in the treatment of cancer.