University of St Andrews

Project description

In a number of proteins, cysteine and glutamine residues can form backbone cross-links via thioester bonds, R-S-C(O)-R'.These bonds are very reactive and can be used, e.g. to promote covalent binding of the protein to nucleophilic groups on cell surfaces (e.g. carbohydrates). State-of-the-art computational methods, including quantum-mechanical/molecular-mechanical techniques [1], will be used to model the mechanisms of thioester formation and -cleavage, calling special attention to effect of the protein environment. The possible catalytic role of neighbouring residues can be identified, furnishing insights into the molecular basis of this potential binding mode of bacterial surface proteins.

Availability

Co-tutelle PhD (12 months UK, 24 in Brazil)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Michael Bühl (School of Chemistry, St Andrews)

• Brazilian University Supervisor(s):

  Prof José Walkimar de M. Carneiro (Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista, s/n, 24020-150 Niterói - RJ, Brazil)

Additional notes

To understand the chemical processes underpinning biological processes at an atomic level is a major driver for the biomolecular sciences. We wish to apply state-of-the-art modelling tools rooted in quantum chemistry to shed light on key aspects in this area, focusing to the detailed mechanism of spontaneous or enzymatic reactions of proteins. M. Bühl and Prof Carneiro have strong links, which has resulted in the following joint publication: M. T. de M. Cruz, J. W. de M. Carneiro,D. A. G. Aranda, M. Bühl, J. Phys. Chem. C 2007, 111, 11068. References: [1] R. M. Hagan, R. Björnsson, S. A. McMahon, B. Schomburg, V. Braithwaite, M. Bühl, J. H. Naismith, U. Schwarz-Linek, Angew. Chem. Int. Ed. 2010, 49, 8421.

Start date

September 2012 or February 2013

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Project description

Radiosensitisers are substances that increase the sensibility of hypoxic cells to radiation, enhancing treatment efficiency in cancer radiotherapy. Complexation to transition metals can enhance this effect, Prime tools for characterisation are NMR and EPR spectroscopy for dia- and paramagnetic complexes, respectively. We propose to use state-of-the-art quantum-chemical methods to model structures, energies, and spectroscopic properties of a variety of metal complexes (including Re(CO)₃⁺ and Cu²⁺ complexes, which have attracted recent interest), calling special attention to the effect of the solvent, water. The results promise insights into speciation of such complexes under physiological conditions, which can help to design novel metallodrugs.

Availability

Co-tutelle PhD (12 months UK, 24 in Brazil)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Michael Bühl (School of Chemistry, St Andrews)

• Brazilian University Supervisor(s):

  Prof Teodorico C. Ramalho (Universidade Federal de Lavras, Campus Universitário - UFLA, Dept. de Química, 37200-000, Lavras-MG,Brasil)

Additional notes

To understand the chemical processes underpinning biological processes at an atomic level is a major driver for the biomolecular sciences. We wish to apply state-of-the-art modelling tools rooted in quantum chemistry to shed light on key aspects in this area, calling special attention to structural properties that can be probed with spectroscopic techniques. M. Bühl and Prof Ramalho have close links, which has resulted in the following two joint publications: T. C. Ramalho, M. Bühl, Magn. Reson. Chem., 2005, 43, 139; T. C. Ramalho, M. Bühl, J. D. Figueroa-Villar,R. B. de Alencastro, Helv. Chim. Acta 2005, 88, 2705.

Start date

September 2012 or February 2013

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Project description

Radiosensitisers are substances that increase the sensibility of hypoxic cells to radiation, enhancing treatment efficiency in cancer radiotherapy. Complexation to transition metals can enhance this effect, Prime tools for characterisation are NMR and EPR spectroscopy for dia- and paramagnetic complexes, respectively. We propose to use state-of-the-art quantum-chemical methods to model structures, energies, and spectroscopic properties of a variety of metal complexes (including Re(CO)₃⁺ and Cu₂⁺ complexes, which have attracted recent interest), calling special attention to the effect of the solvent, water. The results promise insights into speciation of such complexes under physiological conditions, which can help to design novel metallodrugs.

Availability

Co-tutelle PhD (12 months UK, 24 in Brazil)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Michael Bühl (School of Chemistry, St Andrews)

• Brazilian University Supervisor(s):

  Prof Teodorico C. Ramalho (Universidade Federal de Lavras, Campus Universitário - UFLA, Dept. de Química, 37200-000, Lavras-MG,Brasil)

Additional notes

To understand the chemical processes underpinning biological processes at an atomic level is a major driver for the biomolecular sciences. We wish to apply state-of-the-art modelling tools rooted in quantum chemistry to shed light on key aspects in this area, calling special attention to structural properties that can be probed with spectroscopic techniques. M. Bühl and Prof Ramalho have close links, which has resulted in the following two joint publications: T. C. Ramalho, M. Bühl, Magn. Reson. Chem., 2005, 43, 139; T. C. Ramalho, M. Bühl, J. D. Figueroa-Villar,R. B. de Alencastro, Helv. Chim. Acta 2005, 88, 2705.

Start date

September 2012 or February 2013

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Project description

gamma-Aminobutyric acid (GABA) is a key neurotransmitter in the central nervous system. After pioneering studies in St Andrews of synthesis, receptor binding and quantum-chemical modelling of a singly fluorinated analog, higher fluorinated derivatives are currently being explored. We plan to perform high-level quantum-mechanical/molecular-mechanical simulations [1] of such analogs (notably the recently reported 2,3-difluoro-derivative [2]), both in water and the binding pockets of known receptors. We expect detailed insights into the way how the CF bonds affect the conformational preferences of the molecules and, hence, their affinity toward the GABA receptors, informing on potential design of new ligands for therapeutic applications.

Availability

Full PhD (36 months in UK)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Michael Bühl (St Andrews)

• Brazilian University Supervisor(s):

  n/a

Additional notes

The project will benefit from the close proximity of Prof O'Hagan in St Andrews, a world-leading expert in organofluorine chemistry. References: [1] J. Cao, R. Bjornsson, M. Bühl, W. Thiel, T. van Mourik, Chem. Eur. J. 2012, 18, 184. [2] I. Yamamoto, M. J. T. Jordan, N. Gavande, M. RE. Doddareddy, M. Chebib, L. Hunter, Chem. Commun. 2012, 48, 829.

Start date

September 2012 or February 2013

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Project description

The proposed project aims to characterize in detail key components of the nuclear chromosomal DNA replication apparatus of the parasitic protozoa Trypanosoma brucei and Trypanosoma cruzi, and related Leishmania species, and to develop small molecular inhibitors of their functions as potential therapeutics. These organisms are the causative agents of sleeping sickness in sub-Saharan Africa (T. brucei) and Chagas disease in Central and South America (T. cruzi), "Old World" cutaneous leishmaniasis (L. major) and "New World" visceral leishmaniasis (kala-azar) 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; there is an urgent need to identify novel therapeutic targets and to develop effective lead compounds. Surprisingly, despite their importance as disease agents, very little is known of the enzymes and mechanisms of nuclear chromosome replication in kinetoplastid organisms – fewer than a handful of papers have been published in this area and there is vast untapped potential for drug target identification and anti-parasitic drug design. The proposed work aims to use state-of-the-art techniques to determine the molecular composition of the three replicative DNA polymerases in these organisms, to determine the three-dimensional structures of core catalytic domains of each enzyme complex, and to screen pharmacophorically-rich fragment libraries for small molecule inhibitors of their functions as a springboard for future drug discovery.

Availability

Full PhD (36 months in UK)

Supervisers

• University of St Andrews Supervisor(s):

  Dr Stuart MacNeill & Dr Terry Smith

• Brazilian University Supervisor(s):

  n/a

Additional notes

The student will work in the newly built Biomedical Sciences Research Complex (BSRC), a highly interactive multi-disciplinary research facility with a secure containment level 3 facility for parasite culture.

See https://www.st-andrews.ac.uk/bsrc for details.

 

Start date

September 2012 or February 2013

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Project description

Gonadal hormones (such as testosterone and estrogen) can impact upon the development of the brain, leading to sex differences in brain structure and function. While previous research on rodents has shown that the brain is sensitive to the effects of gonadal hormones during prenatal and perinatal periods of life, this project will investigate the hypothesis that adolescence is also a period of life when gonadal hormones influence brain development and subsequent behaviour. Psychopharmacological techniques will be used to suppress gonadal hormones during adolescence in rats, and the effects on long-term behavioural and brain development will be examined. Techniques will include the use of hormone antagonists, ELISA hormone assays, immunohistochemistry and detailed behavioural analysis. The results will provide novel insights into why human males and females are differentially susceptible to a range of mental health disorders.

Availability

Full PhD (36 months in UK)

Supervisers

• University of St Andrews Supervisor(s):

  Dr Gillian Brown (School of Psychology & Neuroscience)

• Brazilian University Supervisor(s):

  n/a

Additional notes

The field of behavioural neuroendocrinology has a strong history in Brazil and is gaining influence at an international level, as exemplified by the First Brazilian International Symposium on Integrative Neuroendocrinology (2011). The student would gain experience of the neuroendocrinology community within the UK through membership of the British Society for Neuroendocrinology. Within St Andrews, the student would become a member of the Institute of Behavioural and Neural Sciences (IBANS), which supports interdisciplinary research across Psychology, Biology, Chemisty and Medicine. In the School of Psychology, PhD students receive advanced training in statistical techniques and experimental design, and all students gain generic skills training. PhD students attend seminars, present their research at conferences and workshops, and often experience public engagement activities, all of which provide an excellent foundation for their future careers.

Start date

September 2012 or February 2013

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Project description

Fluorinated compounds make up 20% of pharmaceutical products. Replacing fluorine for hydrogen does not have a significant steric effect but it suppresses adventitious metabolism, influences pK_a of functional groups and alters solution conformation. The C-F bond is polar and subject to strong stereoeletronic effects. A series of bioactive neurotransmitter analogues will be explored, combining experiment (synthesis, NMR, X-ray) with theory to evaluate the influence of varied fluorine substitution with a focus on neuroactive compounds GABA and NMDA. The student will prepare/synthesise and analyse appropriate compounds in St Andrews and carry out the theory studies in Lavras.

Availability

Co-tutelle PhD (12 months UK, 24 in Brazil)

Supervisers

• University of St Andrews Supervisor(s): Prof David O'Hagan (School of Chemistry, St Andrews)
  
• Brazilian University Supervisor(s):

  Prof Matheus P Freitas (Universidade Federal de Lavras, Campus Universitário - UFLA, Dept. de Química, 37200-000, Lavras-MG,Brasil)

Additional notes

D. O'Hagan has hosted Prof. Freitas during his recent fruitful visit in St Andrews, which, in collaboration with M. Bühl, has resulted in the following two publications: Joint publications: D. O'Hagan, M. P. Freitas, M. Bühl, Chem. Commun., 2011, 48, 2433; M. P. Freitas, M. Bühl,D. O'Hagan, R. A. Cormanich, C. F. Tormena, J. Phys. Chem. A, 2012, 116, 1677.

Start date

September 2012 or February 2013

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Project description

Fluorinated compounds make up 20% of pharmaceutical products. Replacing fluorine for hydrogen does not have a significant steric effect but it suppresses adventitious metabolism, influences pK_a of functional groups and alters solution conformation. The C-F bond is polar and subject to strong stereoeletronic effects. A series of bioactive neurotransmitter analogues will be explored, combining experiment (synthesis, NMR, X-ray) with theory to evaluate the influence of varied fluorine substitution with a focus on neuroactive compounds GABA and NMDA. The student will prepare/synthesise and analyse appropriate compounds in St Andrews and carry out the theory studies in Lavras.

Availability

Co-tutelle PhD (12 months UK, 24 in Brazil)

Supervisers

• University of St Andrews Supervisor(s):

  Prof David O'Hagan (School of Chemistry, St Andrews)

• Brazilian University Supervisor(s):

  Prof Matheus P Freitas (Universidade Federal de Lavras, Campus Universitário - UFLA, Dept. de Química, 37200-000, Lavras-MG,Brasil)

Additional notes

D. O'Hagan has hosted Prof. Freitas during his recent fruitful visit in St Andrews, which, in collaboration with M. Bühl, has resulted in the following two publications: Joint publications: D. O'Hagan, M. P. Freitas, M. Bühl, Chem. Commun., 2011, 48, 2433; M. P. Freitas, M. Bühl,D. O'Hagan, R. A. Cormanich, C. F. Tormena, J. Phys. Chem. A, 2012, 116, 1677.

Start date

September 2012 or February 2013

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Project description

Crick (1984; PNAS81:4586-4590) wrote, “If the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway”. The reticular complex, or thalamic reticular nucleus (TRN), is a sheet of GABA-ergic cells, interposed between thalamus and cortex. It receives collateral projections from both thalamocortical and corticothalamic fibres, but the projections of TRN are only to thalamus. As such, the TRN is privy to the information passing between cortex and thalamus and positioned such that it could filter this information. By its projections into thalamus, the TRN could ‘open’ selected thalamic channels to cortex and close others. Such a function defines the requirements of a substrate of attention. In our studies of the TRN in rats, our aim has been to understand how the brain might solve the problem of selection of inputs with the intention of understanding how and why this might sometimes fail: from errors arising from normal lapses of attention, to functional pathologies of attention arising from brain dysfunction or disease. This project will take a multidisciplinary approach employing behavioural and electrophysiological techniques coupled with pharmacologically selective agents. The aim of the project is to characterize the role played by GABA and nicotine in information transmission in the TRN, with a view to understanding the potential significance of this pathway to the attentional and cognitive deficits in schizophrenia.

Availability

Full PhD (36 months in UK)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Verity J Brown and Dr Eric M Bowman (St Andrews),

• Brazilian University Supervisor(s):

  n/a

Additional notes

n/a

Start date

September 2012 or February 2013

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Project description

Crick (1984; PNAS81:4586-4590) wrote, “If the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway”. The reticular complex, or thalamic reticular nucleus (TRN), is a sheet of GABA-ergic cells, interposed between thalamus and cortex. It receives collateral projections from both thalamocortical and corticothalamic fibres, but the projections of TRN are only to thalamus. As such, the TRN is privy to the information passing between cortex and thalamus and positioned such that it could filter this information. By its projections into thalamus, the TRN could ‘open’ selected thalamic channels to cortex and close others. Such a function defines the requirements of a substrate of attention. In our studies of the TRN in rats, our aim has been to understand how the brain might solve the problem of selection of inputs with the intention of understanding how and why this might sometimes fail: from errors arising from normal lapses of attention, to functional pathologies of attention arising from brain dysfunction or disease. This project will take a multidisciplinary approach employing behavioural and electrophysiological techniques coupled with pharmacologically selective agents. The aim of the project is to characterize the role played by GABA and nicotine in information transmission in the TRN, with a view to understanding the potential significance of this pathway to the attentional and cognitive deficits in schizophrenia.

Availability

Full PhD (36 months in UK)

Supervisers

• University of St Andrews Supervisor(s):

  Prof Verity J Brown and Dr Eric M Bowman (St Andrews),

• Brazilian University Supervisor(s): n/a

Additional notes

n/a

Start date

September 2012 or February 2013

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