PhD studentship with computational Chemistry Team

We are offering a 4 year PhD studentship on the topic Developing in silico Fragment Screening methodologies.

This will be based with the DDU Computational Chemistry Team led by Dr Fabio Zuccotto. Supervisors will be Prof Ian Gilbert and Prof Ulrich Zachariae.

Deadline for submissions is 31st October.

Applications must be made through School of Life Sciences application form. Please contact Dr Zuccotto (f.zuccotto@dundee.ac.uk) for further information.

Background

The process to develop new medicines stars with the identification of small molecules that can modulate a biological target or pathway associated to the disease. In the last twenty years Fragment Based Drug Discovery (FBDD) emerged as a successful alternative to conventional high throughput screening for the generation of chemical hits for drug targets. FBDD offers the advantage of covering larger amounts of chemical space with a relatively small number of different compounds. Due to their smaller size, the molecular fragments are characterized by a limited number of interaction and surface complementarity resulting in a lower affinity to the biological target. Bespoke biophysical detection methods (like Nuclear Magnetic Resonance and Surface Plasma Resonance) are required to identify molecular fragments that bind to the drug target. Structural biology techniques are employed to establish their binding mode and to facilitate their optimization.

The biophysical methods used for screening are very effective in the identification of hit compounds, but their deployment require significant investments both in terms of equipment, logistic and resources reducing their applicability. In Silico approaches can help in addressing those issues and reduce the costs associated to the identification of hits. Several structure-based in silico screening methodologies have been developed in the past to evaluate drug-like molecules but they do not perform well when used to screen molecular fragments. The failure of conventional Molecular Mechanics (MM) scoring functions in assessing molecular interactions in low molecular complexity space being the most critical issue. Capitalising on the research already in progress at the Drug Discovery Unit, the student will combine advanced Computational Chemistry methodologies like Fragment Molecular Orbitals Quantum Mechanics (FMO-QM), Machine Learning and Deep generative modelling to develop a structure-based computational platform for the in silico screening and optimisation of fragments.

References

Daniel A. Erlanson, Stephen W. Fesik, Roderick E. Hubbard, Wolfgang Jahnke & Harren Jhoti. Twenty years on: the impact of fragments on drug discovery

Nature Reviews Drug Discovery volume 15, pages 605–619 (2016)

Heifetz A. et al. (2020) Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method.  Quantum Mechanics in Drug Discovery. Methods in Molecular Biology, vol 2114.

Marcus Olivecrona, Thomas Blaschke, Ola Engkvist, Hongming Chen. Molecular De Novo Design through Deep Reinforcement Learning. https://arxiv.org/abs/1704.07555

Molecular/Cellular Parasitologist

Job reference: SLSC0779

Salary: Grade 7 (£32,817-£40,322)

Closing date: Sunday 4 October

The Mode of Action group (MoA) are seeking to appoint a highly motivated postdoctoral researcher with appropriate skills in molecular and cell biology.

The MoA group, led by Dr Susan Wyllie, is focused on determining the mechanism of action and molecular targets of compounds that are phenotypically-active. To date this work has focused on kinetoplastid and Plasmodium parasites. We have developed an integrated drug target deconvolution strategy, employing an array of established and new methodologies encompassing high-throughput genetics, cell biology and chemical proteomics. We work closely with partners in academia and industry, and information emanating from our studies has been vital in guiding numerous drug discovery programmes.

We have recently received funding to broaden our scope to include drug target identification in Cryptosporidium. You will be dually appointed as a member of the MoA group, and a member of the Pawlowic lab, led by Dr Mattie Pawlowic. The Pawlowic lab create genetic and biochemical tools to investigate parasite transmission. They also collaborate with the MoA group and the Drug Discovery Unit to apply genetic tools to drug discovery.

You will benefit from being a member of both the Mode of Action and Pawlowic labs, and be at the forefront of developing molecular and cell biology tools to support drug target deconvolution for Cryptosporidium parasites. You will adopt existing methodologies currently used for target deconvolution in other parasites for use in Cryptosporidium, and you will have the opportunity to create new strategies and technologies for mode of action studies. You will gain skills in genetic manipulation of Cryptosporidium and use these skills to inform drug discovery. You will engage with project partners and contribute to exciting work to advance the development of therapeutics for cryptosporidiosis. As part of WCAIR you will interact with people working on a whole range of scientific disciplines and advanced technologies including mass spectrometry, cell and biochemical assay development, high-throughput screening, medicinal chemistry, in vivo models, and Drug Metabolism & Pharmacokinetics.

Essential skills

• A PhD in a relevant subject, such as parasitology, microbiology or molecular biology.
• Extensive molecular biology experience (DNA/RNA sample preparation, gene cloning, western blots, etc).
• Considerable experience in the culture of category 2 pathogens.
• Computer and data processing/management skills.
• Ability to work both independently and/or as part of a team.
• Good communication skills – written/verbal.
• Track record of publication in peer-related journals.

Highly desirable skills

• Experience in mode of action studies or drug discovery.
• Considerable experience in the culture and genetic manipulation of eukaryotic pathogens using CRISPR work with apicomplexan parasites including Toxoplasma or Plasmodium is highly desired.
• Experience with analysis of “omics” datasets including proteomics, RNA- Seq, or whole-genome sequencing.
• Microscopy (wide-field, confocal, etc).

This position is fixed-term, with funding available from 01 January 2021 until 31 December 2023.

Appointment on the Grade 7 salary scale is dependent upon you having been awarded a PhD. An appointment may be considered if you are shortly expected to be awarded a PhD. The initial appointment would be made as a Research Assistant on the Training Grade 7 salary scale (Spinal Point 25 – 28 £29,176 – £31,866).

For more information please contact Susan Wyllie (s.wyllie@dundee.ac.uk) or Mattie Pawlowic (m.c.pawlowic@dundee.ac.uk) and visit our websites (https://modeofactiondundee.org) and (https://pawlowiclab.org). Applications should be submitted via the Dundee jobs portal (www.dundee.ac.uk/hr/uodrecruitment/jobvacancies/).

The University’s statement on the use of animals in research can be found here: https://www.dundee.ac.uk/research/governance-policy/policyroadmap/statement-on-use-of-animals/

The School of Life Sciences at the University of Dundee is a world-class academic institution with a reputation for the excellence of its research, its high-quality teaching and student experience, and the strong impact of its activities outside academia. With 900 staff from over 60 countries the School provides a dynamic, multi-national, collegiate and diverse environment with state-of-the-art laboratory, technology and teaching facilities.

The University of Dundee is one of the UK’s leading universities – internationally recognised for our expertise across a range of disciplines and research breakthroughs in multiple areas, including science, medicine and engineering, amongst many others. Conveniently located on the banks of River Tay, our main city-centre campus is at the heart of Dundee – an up-and-coming, friendly, compact and affordable city with a rich heritage in design and technology. Just a short walk from the V&A Museum of Design Dundee, we’re close to both the train and bus stations. We also have campuses at Ninewells Hospital and in Kirkcaldy which are easily accessible via local transport links.

The diversity of our staff and students helps to make the University of Dundee a UK university of choice for undergraduate, postgraduate and distance learning. Family friendly policies, staff networks for BME, Disabled and LGBT staff, membership of Athena SWAN, the ECU Race Equality Charter and Stonewall, as well a full range of disability services, create an enjoyable and inclusive place to work.

Cell Biology Team Leader

For further information about this position please contact Professor David Gray at d.w.gray@dundee.ac.uk. To find out more about the Drug Discovery Unit please visit our website.

The Drug Discovery Unit (DDU)  is a fully integrated drug discovery operation based within a world class Life Sciences research environment. The DDU works on both validation of novel drug targets across a range of therapeutics areas and developing new medicines for neglected diseases (TB, malaria, cryptosporidiosis, leishmaniasis and Chagas disease). The DDU works to Biotech style philosophy and standards, incorporating dynamic, goal driven project management. The DDU has a proven track record of partnering/licencing new drug targets with industry and delivering pre-clinical candidates for neglected diseases.

The School of Life Sciences at the University of Dundee is a world-class academic institution with a reputation for the excellence of its research, its high quality teaching and student experience, and the strong impact of its activities outside academia. With 900 staff from over 60 countries worldwide the School provides a dynamic, multi-national, collegiate and diverse environment with state-of-the-art laboratory, technology and teaching facilities.

A few facts about The School of Life Sciences at Dundee:

• The School of Life Sciences has over 900 research and support staff from 59 countries and external funding in excess of £40 million per year.
• Dundee has twice been named ‘the best place to work in Europe’ in a poll of scientists conducted by The Scientist magazine.
• The School of Life Sciences has been consistently rated ‘5-star’ (the highest rating) by the UK national Research Assessment Exercise.

Dundee, set on the east coast of Scotland, lies in an area of outstanding natural beauty, including large sandy beaches and challenging hills. Dundee is also a vibrant cultural centre. Home to the new V&A Dundee, opened in September 2018 and already hosting its 500,000 visitor; the Dundee Rep and Scottish Dance Theatre; Dundee Contemporary Arts; MacManus Gallery and many individual artists.

For further information about the local area and the top reasons to live and work in Dundee and Scotland;

https://www.seedundee.com/category/see

https://www.visitscotland.com/ebrochures/en/what-to-see-and-do/perthshireanddundee

https://www.talentscotland.com/live/lifestyle/top-reasons-to-live-and-work-in-scotland

The diversity of our staff and students helps to make the University of Dundee a UK university of choice for undergraduate, postgraduate and distance learning. Family friendly policies, staff networks for BME, Disabled and LGBT staff, membership of Athena SWAN, the ECU Race Equality Charter and Stonewall as well a full range of disability services, create an enjoyable and inclusive place to work.

Senior Biologist (Tuberculosis)

The Drug Discovery Unit have an exciting and challenging opportunity for a highly motivated and experienced biologist to join our drug discovery team. The appointee will be involved in leading the biology aspects of a portfolio of drug discovery projects for tuberculosis (TB). They will be responsible for integrating results from our TB biology collaborators with the chemistry, computational chemistry and pharmacokinetic aspects of the program. The successful candidate will gain valuable experience in working with some of the world’s leading TB biologists as part of the TB Drug Accelerator, a unique collaboration between industry and academia aiming to identify novel TB therapeutics.

The TB Portfolio ranges from hit ID, using both phenotypic and target-based approaches, through to identification of pre-clinical candidates, carried out by a team of ~15 scientists and enabled by ~$8 million of funding and multiple international collaborations with Pharma companies and leading research organisations. Currently the project has a range of projects from candidate selection phase and late lead optimisation to hit validation and target-based screening.