SULSA PhD Studentship in Structure-based Drug Design / Molecular 
Modeling / X-ray crystallography: Structure-based design of 6PGDH 
inhibitors, a target for African sleeping sickness

A fully-funded PhD project in the University of Dundee / School of Life 
Sciences in the group of Dr. Ruth Brenk is now available. The project is 
a funded by SULSA and a collaboration with Ian Gilbert (University of 
Dundee) and Mike Barett (University of Glasgow).

Human African trypanosomiasis is a disease with an urgent need for the 
development of better drugs. A promising target is 6-phosphogluconate 
dehydrogenase (6PGDH) which has been validated genetically and 
chemically. Potent substrate-like inhibitors have been synthesised but 
they suffer from a lack of in vitro antiparasitic activity This is 
probably due to the high polarity of these compounds. Consequently, 
various phosphate prodrugs have been investigated and two trypanocidal 
compounds where identified. Despite these promising results stability 
issues remain. An alternative approach is to develop compounds with 
better intrinsic drug-like properties. The available crystallographic 
data enables a structure-based design approach to achieve this goal. An 
initial virtual screening has been carried out and a variety of 
inhibitors has been identified. The project aims to characterize these 
hits in terms of determination of inhibition constants for parasitic and 
human 6PGDH and determination of binding modes by use of X-ray 
crystallography. Based on these results more potent analogues will be 
designed.

This project will expose the student to a wide range of methods (protein 
purification, crystallisation, crystal structure analysis, enzyme 
kinetics, structure-based design, synthesis planning) and would fit a 
student with a background in the area of life sciences and a strong 
interest in protein-ligand interactions.

The 5* research rated School comprises 70 Research Groups and 700 staff 
from 51 countries. Dundee, set on the east coast of Scotland, lies in an 
area of outstanding natural beauty, including large sandy beaches and 
challenging hills. Rainfall charts show this is one of the most sunny & 
dry places in the UK.

Further details are available from Dr. Ruth Brenk ([log in to unmask], 
+44 (0)1382 386230).

To apply, please send a CV and details of at least two referees to Gail 
Guild
([log in to unmask]), Postgraduate Administrator, School of Life Sciences,
MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH.
The starting date is flexible.

-- 
Dr. Ruth Brenk
Biological Chemistry and Molecular Microbiology
School of Life Sciences
University of Dundee
Dow St.
Dundee, DD1 5EH
U.K.
+44 (0)1382 386230 (phone)
+44 (0)1382 386373 (fax)
http://www.brenkgroup.dundee.ac.uk
http://www.dundee.ac.uk/biocentre/SLSBDIV1rb.htm