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Andrew Thompson

Dr

  • 5 WEST 2.15

Accepting Doctoral Students

20002016

Research output per year

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Personal profile

Research interests

Studies on the DNA Duplex Adducts of Anti-cancer agents by High Field NMR

The central target of my research is aimed at determining the molecular basis for the anti-tumour activity of DNA interactive anti-cancer ligands. It is hoped that we will be able relate the structural changes in local DNA structure which are induced or entrapped by these ligands to the biochemical and biological effects and incorporate these findings into the design of future DNA interactive anti-cancer ligands.

A number of methods are available to study the structure and nature of ligand-DNA adducts, these include X-ray diffraction, high-field NMR, circular dichroism, Raman spectroscopy, UV, IR, gel electrophoresis and enzymatic probes. My research has concentrated on the use of high-field NMR coupled with molecular modelling to closely study the duplex adducts formed in the reactions of DNA alkylating ligands and DNA duplexes.

High field NMR studies are performed on the in-house Varian 600MHz and 400Mhz NMR spectrometers and a typical range of two-dimensional experiments are employed including NOESY, ROESY, TOCSY, PE-COSY, DQF-COSY, 1H-31P HMBC and 1H-15N HMBC (where 15N labelled adducts were available). Data from these experiments is used to confirm molecular connectivity and provide insight into bond angles and DNA sugar conformations. They also provide via NOESY spectroscopy accurate through-space distances between protons on neighbouring substituents.

This NOESY (distance) and COSY (angle) data is then interpreted by programs such as MARDIGRAS, SPHINX-LINSHA and PSEUROT in order to generate accurate 1H-1H distances and bond torsional angle restraints which are used to drive extensive molecular modelling studies. Molecular modelling studies involve both unrestrained and restrained mechanics and dynamics calculations using Sybyl / AMBER on Silicon Graphics R12000 workstations. Results of these calculations were then examined both visually by MIDAS Plus and MD Display or with the aid of software tools like DIALS AND WINDOWS to confirm and visualise the structural data obtained.

Current targets that we are interested in investigrating include the unique DNA quadraplex found in the telomers of DNA, and the study of larger adducts incorporating partially (or fully) deuteraterated protein fragments by on to allow complete assignment of the adduct and the use of DOSY NMR spectroscopy to study the interactions of weaker DNA interactive ligands that do not form stable duplex adducts.

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Projects

Research Output

Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases

Nathubhai, A., Haikarainen, T., Hayward, P. C., Munoz-Descalzo, S., Thompson, A. S., Lloyd, M. D., Lehtio, L. & Threadgill, M., 8 Aug 2016, In : European Journal of Medicinal Chemistry. 118, p. 316-327 12 p.

Research output: Contribution to journalArticle

Open Access
File
  • 16 Citations (Scopus)
    141 Downloads (Pure)

    Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

    Paine, H. A., Nathubhai, A., Woon, E. C. Y., Sunderland, P. T., Wood, P. J., Mahon, M. F., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Narwal, M., Lehtio, L. & Threadgill, M. D., 1 Sep 2015, In : Bioorganic and Medicinal Chemistry. 23, 17, p. 5891-5908 18 p.

    Research output: Contribution to journalArticle

    Open Access
    File
  • 15 Citations (Scopus)
    920 Downloads (Pure)

    Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems

    Twum, E. A., Nathubhai, A., Wood, P. J., Lloyd, M. D., Thompson, A. S. & Threadgill, M. D., 1 Jul 2015, In : Bioorganic and Medicinal Chemistry. 23, 13, p. 3481-3489

    Research output: Contribution to journalArticle

    File
  • 2 Citations (Scopus)
    241 Downloads (Pure)

    Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases

    Kumpan, K., Nathubhai, A., Zhang, C., Wood, P. J., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Lehtio, L. & Threadgill, M. D., 1 Jul 2015, In : Bioorganic and Medicinal Chemistry. 23, p. 3013-3032

    Research output: Contribution to journalArticle

    File
  • 21 Citations (Scopus)
    288 Downloads (Pure)