Projects per year
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.
Expertise related to UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):
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Collaborations and top research areas from the last five years
Projects
- 4 Finished
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Refinement of a Polymeric System Delivering CGIs to Prostate Tumours
Threadgill, M. (PI), Lloyd, M. (CoI) & Thompson, A. (CoI)
1/10/14 → 30/09/17
Project: UK charity
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Inhibitors of Tankyrase-1, A Dual-Function Target in the Cancer Cell
Threadgill, M. (PI), Lloyd, M. (CoI) & Thompson, A. (CoI)
1/04/10 → 30/06/13
Project: UK charity
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A New Approach to Delivery of Super-Potent Drugs to Prostate Tumours
Threadgill, M. (PI), Lloyd, M. (CoI) & Thompson, A. (CoI)
1/10/09 → 30/09/12
Project: UK charity
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Sirtuins as Targets for Cancer Therapy
Threadgill, M. (PI), Acharya, R. (CoI), Lloyd, M. (CoI) & Thompson, A. (CoI)
1/05/08 → 31/07/10
Project: UK charity
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Transparent, Sprayable Plastic Films for Luminescent Down-Shifted-Assisted Plant Growth
Müller, R., Okokhere-Edeghoghon, B., Janowicz, N. J., Bond, A. D., Kociok-Kohn, G., Cox, L. M. R., Garzon, D., Waine, T. W., Truckell, I. G., Gage, E., Thompson, A. J., Busko, D., Howard, I. A., Saavedra, M. S., Richards, B. S., Breiner, B., Cameron, P. & Wright, D. S., 6 Nov 2024, (E-pub ahead of print) In: Advanced Materials Technologies. 9 p., 2400977.Research output: Contribution to journal › Article › peer-review
Open Access -
Precursors and correlates of transient and persistent longitudinal profiles of psychotic experiences from late childhood through early adulthood
Rammos, A., Sullivan, S. A., Kounali, D., Jones, H. J., Hammerton, G., Hines, L. A., Lewis, G., Jones, P. B., Cannon, M., Thompson, A., Wolke, D., Heron, J. & Zammit, S., 30 Jun 2022, In: The British Journal of Psychiatry. 220, 6, p. 330-338 9 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile5 Citations (SciVal)51 Downloads (Pure) -
STATE OF THE CLIMATE IN 2021
State of the climate , 25 Aug 2022, In: Bulletin of the American Meteorological Society. 103, 8, p. S1-S465 471 p.Research output: Contribution to journal › Article › peer-review
Open Access35 Citations (SciVal) -
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 journal › Article
Open AccessFile25 Citations (SciVal)357 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 Sept 2015, In: Bioorganic and Medicinal Chemistry. 23, 17, p. 5891-5908 18 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile27 Citations (SciVal)1186 Downloads (Pure)