School of Chemistry and Dept. of Biochemistry, University of Bristol

An Industrially Sponsored Studentship, Combining Modelling and Experiment

In collaboration with Dr. Andrea Hadfield, Dept. of Biochemistry

A major challenge in drug development is to avoid metabolic and toxicity problems caused by the interaction between potential pharmaceutical leads and cytochrome P450s. These key metalloenzymes metabolize foreign compounds for excretion from the body. An understanding of the interactions between potential drugs and human P450s would be beneficial not only in the development ofindividual drugs, but also in new screening processes for drug development in general. It is estimated that up to 50% of all known drugs interact with cytochrome P450 3A4, while cytochrome P450 2D6 is estimated to metabolize approximately a third of drgs in current clinial use. Better understanding of the interaction of cytochrome P450s with drugs, and the mechanisms by which these enzyme catalyse their conversion, has the potential to contribute significantly to pharamceutical development and drug design. Modern modelling techniques can contribute signiifcantly to providing the detailed understanding required. For example, combined quantum mechanics/molecular mechanics (QM/MM) methods allow the reactions within the enzyme to be modelled, identifying the mechanism of reaction and the roles of key groups in the proteins. Docking methods can be used to study ligand binding modes. Combinations of these methods will allow the development of new descriptors to correlate with activities, leading to the development of new lead screening methods and drug design strategies. This work will be carried out in collaboration with experimental work in the group of Dr. Andrea Hadfield, Dept. of Biochemistry. The project will combine modelling and experimental approaches to understanding the structure and function of this vital group of enzymes.

Candidates should hold a first or upper second class honours degree in Chemistry, Biochemistry or a related subject.

For more details please contact Dr. Adrian Mulholland,

School of Chemistry,

University of Bristol, BS8 1TS

E-mail: Adrian.Mulholland@bris.ac.uk

Phone : (0117)-928-9097

(0117)-928-8313 (Department Office)

Fax: (0117)-925-1295

http://www.bris.ac.uk/Depts/Chemistry/staff/amulholl.htm

http://www.chm.bris.ac.uk/pt/ajm/adrian.html

http://www.bris.ac.uk/Depts/Chemistry/Bristol_Chemistry.html