Drug design and action
This group focuses on the discovery end of the pharmaceutical sciences. It is active in discovering and developing novel lead-drug candidates and molecular diagnostics using a variety of approaches, including rational drug-design methods and natural sources. The required expertise and facilities are in place for contributions from high-level computational and NMR structural methods through organic synthesis, development of novel analytical approaches, the biochemistry/molecular biology of the drug and other targets systems we work on, right through to the necessary cell biology and physiological studies, both of microbial systems and of tumours in humans.
Methods and computational approaches
The group applies a wide range of methods, especially computational approaches and structure-based design. Targets include both nucleic acids (DNA and RNA) as well as a number of protein and enzyme systems. Structural studies carried out in the group are particularly based on high-field NMR spectroscopic methods, but staff also use X-ray crystallography data from collaborating colleagues both in Manchester and elsewhere, as well as similarity (homology) modelling of proteins. Many of the rational drug design projects use computer-aided methods, such as virtual screening and de novo design techniques.
The group also develops new computational approaches, focusing on molecular dynamics, solvation, hybrid QM/MM methods and carbohydrate modelling. A unique aspect of the group is its recent development of rational structure-based design methods for improving molecular diagnostics and biological probe molecules for use in a range of problems from biochemistry and cell biology through to whole organism physiological systems. To this end the group has formed the Wolfson Centre for Rational Structure-Based Design of Molecular Diagnostics. Building on the complementary expertise and strong research funding of a core of academic staff from across the whole School of Pharmacy, the Wolfson Foundation has provided a substantial grant to ensure that the group has state-of-the-art infrastructure and facilities for this venture which is unique in the UK, if not worldwide. The Centre has now added additional collaborations and projects involving other disciplines such as the Department of Chemistry and overseas laboratories (such as Santana University in Japan).
Drug design
In terms of drug design, candidate molecules are obtained from natural sources especially plants (pharmacognosy) or synthesised in the group's labs, and then tested at a biochemical level against purified targets such as enzymes and proteins, DNA or RNA. Molecular biological approaches to both bacterial and yeast over-expression of cloned target molecules (proteins, RNA) are also used. The next stage is also handled within the group, testing the candidate molecules in more complex biological systems. Thus, we use:
- Cell lines, particularly a number of cancer types
- Various cultures, for example, in-house we work on planktonic and biofilm bacterial preparations
- Trypanosomal, leishmanial and malarial parasite systems by collaboration
- Whole organism models such as tumour xenografts
The group also looks at the identification and validation of novel biological targets. The main disease areas are cancer and anti-infectives drugs (especially against parasites and bacteria).
Anti-cancer strategies
In the cancer area, the group's main effort is to design and develop novel anti-cancer strategies based on abnormalities in tumour physiology. Many tumours contain regions of low oxygen tension (hypoxia), generally thought to arise as a consequence of a poor and disorganised blood supply. Since hypoxic cells are three-fold more resistant to radiation than aerobic cells, the presence of hypoxic cells in human tumours is associated with resistance to treatment with radiotherapy and possibility to many forms of conventional chemotherapy. With core support from a MRC programme (£3.6m, 1996-2005) a team led by Ian Stratford is attempting to exploit the presence of hypoxia in solid tumours to develop new therapeutic strategies.
Other pharmaceutical programmes
The group has other pharmaceutical programmes which interface it with other research groups in the School (eg Drug Delivery, Pharmacokinetics ) and at other leading universities and research institutions in Manchester and the north-west of England, as well as worldwide (the group has especially strong links with Estonia, France, Iran, Japan, Portugal, Russia, Thailand and the USA).
Discovery 2 Medicine (D2M)
As a centre of translation of biological discovery into pharmaceutically usable output, the group has the expertise, either in-house or through its excellent networks, to help academics and companies who have biological lead discoveries, but do not have access to the required facilities or staff for moving closer to commercial proof of principle (eg the group has helped a number of regional biological groups by linking them with computational chemists, NMR structural teams, pharmaceutical formulation experts). This is achieved through Discovery 2 Medicine (D2M), a world class 'Scientific Advisory Board' that provides industrial and academic expertise through an expert review panel and gives advice and mechanisms on how to take projects forward.
For further information, see: Discovery 2 Medicine (D2M) website
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