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Seven four-year drug discovery PhD studentships available
As part of an on-going contribution to Scottish life sciences, MSD, a global healthcare leader, has given a substantial monetary funding to the Scottish Funding Council (SFC) for distribution via SULSA to develop and deliver a high quality drug discovery research and training programme.
The fund, which is backed by additional investment from the SFC and the six SULSA Universities, is launching with a programme for 18 four-year PhD studentships, starting in October 2012.
The PhDs will all be in the field of Drug Discovery, and will benefit from a high-quality training programme, travel and consumables budgets, as well as being integrated into the SULSA network of excellence. All aspects of the programme have been geared towards attaining the highest value in terms of scientific discovery, training and impact.
Applications are invited from outstanding UK and EU students, who hold or expect to gain a first or upper second-class degree or equivalent.
The closing date for applications is 24th August 2012. Successful candidates will receive an annual stipend in line with RCUK rates and payment of their tuition fees. Applicants should be available for interview on selected dates still to be determined during August 2012. These studentships will start on 1st October 2012.
The aim of this PhD studentship will be to understand the effect that antibacterial compounds have on the metabolome (that is the sum of all the metabolites in bacteria), and to see how this information could be used to design more effective antibacterials. The studentship will involve designing and synthesising potentia lantibacterial compounds, testing the compounds against bacteria and seeing the effect of the compounds on the metabolome. We are looking for students with a strong grounding in organic chemistry, with a strong interest in microbiology. Click here for more information.
Analysis of productivity in the pharmaceutical industry identified reducing the cost of lead optimisation as one of the most important factors for improving productivity. Common industry costs for progressing from a target to a hit to a clinical candidate is estimated at $20 million taking 3 to 5 years of which 95% may fail in clinical development. Therefore new methods that can reduce the cost and cycle time of lead optimisation can have a substantial impact on improving the productivity of pharmaceutical research. The goal of the project is develop a new machine learning methods of lead optimisation in medicinal chemistry. We have developed a new method for adaptive drug design by multi-objective evolutionary optimization. The system is designed to evolve novel, patentable chemical structures against multi-target objectives. We have experimentally validated the method in 4 chemistry projects, to date, as a method to generate chemotypes (series of chemical analogues) with specific polypharmaoclogy and ADME profiles. However for first-in-class drug targets or for highly novel chemotypes there is insufficient data to apply machine leaning methods. We proposed to extend the evolutionary optimisation algorithm we have developed to include ‘active learning’, to optimise the order in which compound are designed and tested, in iterative cycles. ‘Actively learning’ or experimental design is an iterative machine learning method that attempts to optimise the building of a classifier, such as a Bayesian active model, by choosing the most informative examples to add to the training set. Active learning attempts to compute the statistically optimum way to acquires data incrementally, at each stage using the model learned so far to help identify especially useful additional data for building a predictive model. Click here for more information.
Biophysical screening of GPCRs - Dr Iva Navratilova
The biophysics of G-protein coupled receptors (GPCRs) - one of the most important classes of drug targets - is currently undergoing a revolution. However, despite the advances in GPCR structural biology, the screening of ligands against GPCRs is usually based on measurements of either ligand displacement or downstream functional responses, rather than direct observation of ligand binding. A biophysical method that directly measures GPCR-ligand interactions, independent of binding site, probe and signalling pathway would be a valuable screening method in drug discovery. Surface Plasmon Resonace (SPR) biosensor assays are widely considered as the most accurate and versatile biophysical screening technology that describes the kinetic aspects of ligand binding. The project is focused on the development of a reliable and robust SPR approach that can be applied to any solubilised GPCR. The goal of the project is to optimise SPR assays for membrane proteins into a method that can be routinely applied to all GPCRs. The project will explore a systematic programme of research that optimises all aspects of the technology from protein expression, choice of protein tags, detergent/lipid matrix composition, immobilisation methods and buffer additives. Click here for more information.
Design, synthesis and screening of miniaturized combinatorial chemical libraries for the discovery of small molecular ligands for the human WD40 domain family - a systems chemical genetics approach - Professor Manfred Auer
It is now clear that regulated protein interactions underpin most if not all aspects of biology (1). Protein interactions are most often mediated by modular protein recognition domains. Molecular domains encoded by the human genome now number in the hundreds of families, however, modular domains have not been systematically targeted for drug discovery. In this project, we will implement a general method to identify small molecules that bind and alter the function of one of the largest modular domain classes in humans, the WD40 domain, which has barely been explored for drug discovery (2). Recent studies suggest that small protein interactors tend to engage surface hotspots that mediate physiologically relevant protein interactions (3). Biomedically important human WD40 domain proteins include over 20 different F-box proteins, target of rapamycin (TOR) kinase complex subunits and Gb-subunits of heterotrimeric G proteins, amongst many others (2). A PhD student will undertake the design and synthesis of 6 tagged one-bead one-compound libraries targeted specifically to possible small molecule binding pockets of WD40 domains with known structures. As a second main task the student will produce an extensive collection of WD40 domain-fluorescent protein (FP) fusions. The collection of WD40 domain fusions will be screened on-bead in cell lysates and in mixtures by the student using the CONA technique, a confucal and ultra-high throughput bead-based screening method on proprietory micro-spectroscopes and the OPERA HCS system (4,5). The student will also undertake hit compound identification, characterization in phenotypic assays and structure co-determination. This project will be jointly supervised by Professor Manfred Auer and Professor Mike Tyers, giving the student a true interdisciplinary experience and the possibility to work with leading research groups at the Universities of Edinburgh, Montreal and Toronto. Due to the nature of the library synthesis a chemistry background is essential. Click here for more information.
(1) Pawson T. (1995) Protein modules and signalling networks. Nature 373: 573-580;
(2) Stirnimann, CU, Petsalaki, E, Russell RB and Muller CW (2010) WD40 proteins propel cellular networks. Trends Biochem Sci 35: 565-574;
(3) Orlicky S, Tang X, Neduva V, Elowe N, Brown ED, Sicheri F and Tyers M (2010) An allosteric inhibitor of substrate recognition by the SCF (Cdc4) ugiquitin ligase. Nat Biotechnol 28: 733-737;
(4) Hintersteiner M, Kimmerlin T, Kalthoff F, Stoeckli M, Garavel G, Seifert JM, Meisner, NC, Uhl V, Buehler C, Weidermann T and Auer M (2009) Single bead labeling method for combining confocal fluorescence on-bead screening and solution validation of tagged one-bead one-compound libraries. Chem Biol 16: 724-735;
(5) Hintersteiner M, Buehler C, Uhl V, Schmied M, Muller J, Kottig K and Auer M (2009) Confocal nanoscanning, bead picking (CONA): PickoScreen microscopes for automated and quantitative screening of one-bead one-compound libraries. J Comb Chem 11: 886-894.
Combining stem cell technologies, in-silico design, synthesis of large scale combinatorial chemical libraries on microbeads, and high-throughput screening to find new lead compounds for Parkinson's disease - Professor Tilo Kunath
The small intrinsically disordered protein, alpha-synuclein drives the initiation and progression of Parkinson's disease (PD). This PhD project will use in-silico methods to design and then synthesize tagged one-bead one-compound libraries  specifically targeting alpha-synuclein. The cellular target will be PD neurons from induced pluripotent stem cells (iPSCs) established from a patient with triplication of the gene encoding alpha-synuclein, which causes severe early-onset Parkinson’s , and transgenic human embryonic stem cells (hESCs) over-expressing alpha-synuclein. Differentiated neurons from these hESCs exhibit a severe mitochondrial defect. The student will establish high-throughput screening protocols for these human stem cell-derived PD neurons using the OPERA high-content screening system from PerkinElmer. Confirmed hits from this screen have the potential to be disease-modifying drugs for Parkinson’s. This project will be jointly supervised by Dr. Tilo Kunath and Prof Manfred Auer, giving the student a true inter-disciplinary experience. Due to the nature of the library synthesis a chemistry background is essential. Click here for more information.
1. Hintersteiner M, Kimmerlin T, Kalthoff F, Stoeckli M, Garavel G, Seifert JM, Meisner NC, Uhl V, Buehler C, Weidemann T, Auer M. (2009) A single bead labelling method for combining confocal fluorescence on-bead screening and solution validation of tagged one- bead one-compound libraries. Chemistry & Biology 16, 724-735.
2. Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T. (2011) Parkinson's disease induced pluripotent stem cells with triplication of the alpha- synuclein locus. Nat Commun. 2, 440.
The traditional method of finding candidate drug molecules involves screening thousands of natural and synthetic molecules often guided by medicinal chemistry tools. However, such techniques lead to the isolation of false positives and/or non-drugable hits. An alternative strategy would be to use the target molecule itself (e.g. protein) to template the synthesis of a potent inhibitor. We use dynamic covalent chemistry (DCC) to generate dynamic combinatorial libraries (DCLs). DCC uses reversible chemical reactions to set up an equilibrating network of molecules at thermodynamic equilibrium, which can adjust its composition in response to external agents. A DCL is thus adaptive and capable of evolutionary behaviour. We made exciting early breakthroughs in this area (Shi et al, J. Am. Chem. Soc., 128, 8459, 2006). Recently we synthesised a hydrazone library in the presence of the important detoxification enzyme glutathione S-transferase (GST). Each GST isoform (from a parasitic worm, GST SJ and one human GST P1-1) amplified a single, but different, molecule from the pool of the 10-member DCL. In essence, each GST selected its best binder from the library. Our work was published and highlighted in Nature Chemistry (Bhat et al., Nature Chemistry, 2, 490, 2010 & Miller, News and Views). This new project aims to further develop this platform generating new DCLs focused at other drug targets. The candidate should have a strong background in chemistry and/or biochemistry and will be trained in protein chemistry, enzyme assay, in vivo assays, tissue culture, microbiology and synthetic chemistry. It will be based at the University of Edinburgh. Click here for more information.
The project aims to characterize in detail the replicative DNA polymerases Pol _, Pol _ and Pol _ of the parasitic protozoa Trypanosoma brucei and Trypanosoma cruzi, and related Leishmania species, allowing development of small molecule inhibitors of their functions as novel therapeutics. These organisms are the causative agents of sleeping sickness in sub-Saharan Africa (T. brucei), Chagas disease in Central and South America (T. cruzi), and cutaneous and visceral leishmaniasis in East Africa, South America and Southeast Asia (various Leishmania species). The diseases caused by these parasites affect millions of people and represent a huge percentage of the world's disease burden; as such, there is an urgent need to identify novel therapeutic targets and to develop compounds that kill the parasites. Initially, each of the three polymerases will be purified from T. brucei, allowing determination of their subunit compositions. The in vivo properties of individual subunits will be analysed using RNA interference and fluorescence epitope tagging, allowing the validation of these enzymes as drug targets. Small molecule libraries will then be screened using a variety of state-of-the-art techniques to identify inhibitors of each of the three polymerases. Primary hits will be characterised further by direct activity assays. Further screening of commercially available analogues will allow compound structure-activity relationships to be determined and lead towards the identification of potent lead compounds. Finally, but crucially, lead compounds will be tested for their ability to inhibit trypanosomal growth by blocking chromosome replication and cell cycle progression. The project will involve interaction between the main supervisor's group and those of Dr Terry Smith and Prof. Jim Naismith, all within the new BRSC building, a highly interactive multi-disciplinary research facility with a containment level 3 facility for parasite culture and the Scottish Structural Proteomics Facility. Click here for more information.
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