OUR CAPABILITIES

Our parasitology groups undertake the spectrum of activities associated with target validation through to mechanism of action and resistance studies of active agents.

Techniques routinely employed include: gene knockout and RNAi; target cloning, expression and purification; mechanistic and structural characterization; and in vitro and in vivo compound evaluation against mammalian stages of Trypanosoma brucei subspecies, T. cruzi, and Leishmania species.

Computational chemistry covers a variety of different tasks within the DDU. This group is involved with activities such as compound library selection, analysis of hits from screening and various approaches for drug design.

This includes virtual screening, pharmcophore searching and compound design using protein structures. Work also involves constructing homology models of proteins and druggability assessment of potential molecular targets. Work is also carried out to make use of chemoinformatics in our discovery processes.

Hit Discovery in the DDU comprises a state of the art screening facility with a comprehensive range of liquid handling and detector technology capabilities. Commonly used assay platforms include absorbance, fluorescence intensity, fluorescence polarisation , TRF / HTRF, luminescence, alphascreen and all radiometric read-outs.

To support cell-based screening platforms, in particular, we have dedicated Cat 2 and Cat3 tissue culture facilities; fully automated robotics allowing compound handling and plate processing in a clean environment and automated microscopy. (InCell Analyser 1000- fluorescence and transmitted light)

Our bespoke collections of lead-like compounds include both diverse and target focused sets. We also have a commercially available whole genome siRNA screening library. For more information on our compound collections, please Click Here.

We have a medicinal chemistry team with a large amount of experience from the Pharmaceutical/ Biotech sector.

The chemists work on hit validation, hit to lead chemistry and lead optimisation.

The chemists occupy new and modern laboratories.

Chemistry specific equipment includes three NMR spectrometers, LC-MS, various automated chromatography equipment, equipment for parallel synthesis, microwave reactors, etc.

The medicinal chemists works as an integrated unit with other colleagues from the DDU.

Facilities are available for all aspects of protein crystallography enabling the characterization of accurate structures of target enzymes in complex with inhibitors.

Laboratory facilities are available for protein production and purification, there is a dedicated crystallisation laboratory plus crystallisation robot (Phoenix), two Rigaku-MSC rotating anode image plate systems plus block allocation grants to access the European Synchrotron Radiation Facility in Grenoble, and also Diamond, UK.

These capabilities are further underpinned by computing facilities for all aspects of structure determination, biophysical characterisation and analysis plus molecular modeling.

The DMPK group at Dundee has implemented industry standard assays coupled with state of the art LCMSMS technology for supporting hit to lead and lead optimisation programmes.

The capabilities now available at Dundee include in silico ADME models together with a range of in vitro and in vivo tools, selected in order to provide a good overall assessment of the developability profile of compounds early in the lead optimisation process.

Metabolic stability (intrinsic clearance) of a new compound can be investigated using microsomes, hepatocytes or cytosol from a range of preclinical species and human. The drug-drug interaction and bioactivation risk for a new compound is investigated using human liver microsomes, evaluating CYP450 inhibition and metabolism dependent inhibition, together with a glutathione trapping assay to assess the bioactivation potential. In addition, a reaction phenotyping assay is available to give a preliminary understanding of the enzymology involved in the metabolism of a new compound.

A further in vitro assay that has been implemented at Dundee is 96 well equilibrium dialysis for the assessment of plasma protein and brain tissue binding of new compounds. This allows for correction to the free plasma and free brain concentration, both of which may be more meaningful indicators of the true efficacious concentration of a molecule and so aid in understanding of PK/PD relationships.

Together with these in vitro assays, the DMPK group at Dundee also has the capability to perform in vivo pharmacokinetic, brain penetration and Pgp interaction studies in rodents, usually mice. The group has the expertise to perform serial blood sampling in mice so that a full PK profile can be obtained from a single animal. Additionally the group can provide PK/PD support using a number of dose routes and is working very closely with biology in order to build a better understanding of the PK/PD relationship within each programme.