Head of Division: Professor Alan Fairlamb Divisional secretaries: Ms Kate Scott (JBC) Mrs Claire Kadoch (WTB) Deputy Head of Division Professor Ian Gi

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1 Research in the Division of Biological Chemistry and Drug Discovery

2 Head of Division: Professor Alan Fairlamb Divisional secretaries: Ms Kate Scott (JBC) Mrs Claire Kadoch (WTB) Deputy Head of Division Professor Ian Gilbert Lab managers: Ms Shona McInroy (WTB) Mr Brian Weryk (JBC) Principal Investigators Innovation, Synergy, Discovery The overarching theme of the Division is the discovery of chemical solutions to biological problems through excellence in basic and applied multidisciplinary research. Discovery, characterization and validation of drug targets in neglected diseases such as trypanosomiasis, leishmaniasis, malaria and other bacterial pathogens is a major research focus. Knowledge gained from these fundamental studies forms the foundation for translation into novel drug-like leads through a combination of high throughput screening, structure based design and medicinal chemistry. We also have an interest in discovering small molecules that influence stem cell fate in order to develop specific cell types for drug discovery. To meet these challenges in basic and translational research, members of the Division include specialists in bioinformatics, enzymology, molecular biology, glycobiology, in vitro and in vivo pharmacology and synthetic organic and medicinal chemistry. Professor Geoff Barton Professor of Bioinformatics and Co-Director of the Post-Genomics and Molecular Interactions Centre Computer prediction of protein structure and function Our research centres on the development and application of computational techniques to aid understanding of biological systems. We are known for methods for sequence analysis (Jalview) and protein structure prediction (JPred) but we also develop computational techniques to interpret large collections of biological data. For example, the PIPS algorithm predicts protein-protein interactions by exploiting information from diverse sources within a common Bayesian framework. We collaborate with experimentalists carrying out transcriptome, genome or proteome-wide experiments. Current research ranges across many species and systems including the genome-wide analysis of alternative polyadenylation in Arabidopsis, through to the understanding of processes controlling protein expression in human liver disease.

3 Dr Ruth Brenk Lecturer Structure based drug design The overall research goal of the Brenk group is to improve methods used for structure-based drug design and to apply these methods to design inhibitors for enzymes with biological relevance. A key point in our research is the interplay of theoretical and experimental methods. Currently, we are working on the following topics: 1. Drugs for neglected diseases. We deal with all aspects of computational chemistry in the tropical disease initiative. 2. RNA-ligand docking. We are using riboswitches as model systems to test and improve RNA-ligand docking. 3. Structure-based inhibitor design. In collaboration with other lab. Professor Alan Fairlamb Wellcome Principal Research Fellow and Professor of Biochemistry Biochemical drug targets in parasites Activities in the Fairlamb group involve multidisciplinary approaches to the discovery and development of better drug treatments for neglected tropical diseases caused by parasitic trypanosomes and leishmania. Typically this involves: identification of druggable enzyme targets; their expression and characterization at the molecular level; validation using genetic and chemical tools to knockdown or knockout the target; and assay development for drug discovery. We also study the mode of action of existing drugs and novel trypanocidal compounds identified by phenotypic screening and the mechanisms by which parasites acquire resistance. PhDs generally involve training in molecular biology, biochemistry, cell biology and organic chemistry. Professor Michael Ferguson Professor of Molecular Parasitology and Dean of Research Parasite surface molecules protect the organisms and enable them to infect both the insect vector and the animal host Our research is multi-disciplinary and involves defining: (a) the structural repertoire of parasite glycoproteins (b) the biosynthetic repertoire of necessary glycosyltransferases and processing enzymes needed to create the structural repertoire and (c) the metabolic repertoire of sugar nucleotides needed to fuel the biosynthetic repertoire. We use genetic manipulation of the parasites, sophisticated biochemical, mass spectrometric and proteomic methodologies, microscopy and synthetic organic chemistry to perform these studies and to provide validated drug targets for entry into our Drug Discovery Unit. Professor Ian Gilbert Professor of Medicinal Chemistry Medicinal chemistry Dr David Gray Head of Biology Drug Discover Unit My research interests are in medicinal chemistry, the design and synthesis of potential therapeutic agents. As Head of Chemistry in the Drug Discovery Unit at the College of Life Sciences. I have a particular focus on drug discovery for neglected tropical diseases such as human African trypanosomiasis and malaria. I am also interested in developing novel paradigms and approaches to drug discovery. The biology team within the Drug Discovery Unit have considerable drug discovery expertise and an in-depth knowledge of biochemistry, cell physiology and the pharmacology of diverse protein target classes. We have access to industry-standard liquid handling and reader technology. We aim to combine our knowledge, experience and hardware to answer the questions that will enable the identification and progression of effective compounds to the clinic. As a pharmacologist, I am interested and excited by the opportunities of looking for new ways to modulate the activity of proteins, particularly by looking for allosteric interactions and using the developing systems knowledge to identify and modulate relevant signalling pathways.

4 Professor Andrew Hopkins Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology Biosensor-based Drug Discovery Our lab is interested in developing surface plasmon resonance as a powerful screening method in drug discovery. We have a state-of the-art biosensor lab equipped with Biacore 4000, T100 and 3000 instruments, enabling the lab to be highly efficient in biosensorbased fragment screening. We are one of the leading groups in the world in development of biosensor screening methods for membrane proteins, including GPCRs. A keen interest of the lab is the discovery and analysis of allosteric ligands for GPCRs and protein kinases. Professor Bill Hunter Professor of Structural Biology Protein crystallography applied to enzyme targets for structure-based drug design The Hunter laboratory works at the interface of chemistry, biology and biomedicine. We combine crystallographic methods with other technologies to study molecular structure and interactions to investigate key biological processes; to understand how drugs work and to underpin early stage drug discovery. We study unusual enzyme catalysed reactions in essential pathways such as lipid/isoprenoid biosynthesis targeting pathogens such as Kinetoplastid and Apicomplexan parasites, which present major problems in developing countries. More recently therapeutic targets in Gram-negative bacteria have been characterised and a new project involves assembly and function of complex protein folding and secretion pathways. Dr David Martin Scientific Officer High Throughput Phosphoproteomic Analysis; Sequencing the Potato Genome We develop novel methods for high throughput analysis of phosphoproteomics data. This helps understand the molecular chatter that controls how proteins in the cell are switched on and off. I am also analysing the sequence of the potato genome using massively parallel DNA sequencing and developing methods to predict what task is performed by the individual genes in the potato.the techniques at the core of our research enable the development of tools that give us the ability to handle and interpret massive quantities of data. These let us work with our collaborators to identify novel biological insights. Dr Iva Navratilova Independent Investigator Biosensor-based drug discovery Our lab is interested in developing surface plasmon resonance as a powerful screening method in drug discovery. We have a state-of the-art biosensor lab equipped with Biacore 4000, T100 and 3000 instruments, enabling the lab to be highly efficient in biosensor-based fragment screening. We are one of the leading groups in the world in development of biosensor screening methods for membrane proteins, including GPCRs. A keen interest of the lab is the discovery and analysis of allosteric ligands for GPCRs and protein kinases. Dr Andrei Nikolaev Reader in Organic Chemistry Advanced Carbohydrate Chemistry and Biochemistry My laboratory has an extensive interest in the chemical preparation of biologically important complex carbohydrates. The area of research involves the chemical synthesis of novel glycans, phosphoglycans and glycolipids, which are immunogenic or/and virulence factor macromolecules on the cell surface of protozoan parasites, bacteria and yeasts, and application of these synthetic compounds for biochemical studies, immunological studies and the preparation of synthetic glycovaccines. We ve recently developed the preparation of surface lipophosphoglycans from Leishmania parasite and the methodology for the preparation of neoglycoconjugates composed of the synthetic phosphoglycans and an immunogenic protein carrier. The L. mexicana glycoconjugate was shown to be protective (as a vaccine) in mice against Leishmania infection. We developed novel synthetic strategies for the synthesis of surface glycosylphosphatidylinositols (GPI anchors) from T. cruzi, which allowed their reparation in multi-milligram amounts. The prepared GPIs revealed biological activity like naturally occurring counterparts. We also accomplished the preparation of a truncated GPI anchor of T. brucei, which revealed high acceptor substrate activity for the mannosyltransferase III from T. brucei GPI pathway. A set of analogues of this GPI was prepared and tested as substrates/potential inhibitors for the enzyme. The fine substrate specificity of MT-III was characterized and an effective inhibitor of the enzyme was found. My general goal is elaboration of novel chemical methods for the preparation of complex glycan structures, which are then used as tools to achieve new biological knowledge.

5 Dr Kevin Read Head of DMPK Group Drug metabolism and pharmacokinetics The DMPK group at Dundee has implemented industry standard assays coupled with state of the art UPLCMSMS technology for supporting hit to lead and lead optimisation programmes. In silico models, together with a range of in vitro tools (solubility, intri nsic clearance, plasma and tissue binding, CYP450 inhibition, metabolism dependent inhibition, glutathione trapping) and in vivo tools (serial bleeding in mice by a variety of dose routes, hepatic portal vein sampling in rats, brain penetration studies, mdr1a deficient mice) have been implemented in order to provide a good overall assessment of the developability profile of compounds early in the lead optimisation process. Furthermore, with the need to rapidly validate targets in vivo, HRN TM (CYP450 null) mice and/or implanted osmotic pumps are used in efficacy studies on those targets with poorly optimized chemistry in order to maintain prolonged efficacious free concentration of compound in a mouse without the need for compound optimisation apriori. Professor Paul Wyatt Director of Drug Discovery Drug Discovery for Topical Diseases As Head of The Drug Discovery Unit (DDU) my role is to lead our efforts to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, develop these compounds into potential drug candidates. I have a broad interest in a range of disease areas from neglected parasitic diseases, to mainstream diseases such as cancer. As a medicinal chemist by training, my particular area of interest is the use of structural information, in silico design tools (including predicting pharmacokinetic properties) and informatics to design better drug candidates. (see College of Life Sciences University of Dundee Dundee DD1 5EH Tel: (0)