MSCA PhD students in Chemistry with specialization Organic Chemistry - Hiring in process/Finished, not possible to apply

3 MSCA PhD students in Chemistry with specialization Organic Chemistry

The Department of Chemistry – BMC conducts research and education in analytical chemistry, biochemistry and organic chemistry. More than 100 people, including around 45 PhD students, work at the department. New employees and students are recruited from all over the world and English is the main working language. The department is located at the Biomedical Centre in Uppsala, which facilitates collaborations with research groups in biology, pharmacy, medicine and SciLifeLab and gives access to advanced infrastructure for experimental and theoretical studies. The international environment and good opportunities for interdisciplinary collaborations enables PhD students at the department to participate in relevant research projects and prepare for an international research career.

Read more about the research at The Department of Chemistry – BMC at our website.

Over 50% of human proteins are considered ‘undruggable’ by classical small molecules. Of particular importance are intracellular proteins lacking classical binding pockets. Selective, high-affinity binding to the flat surface of such proteins requires larger molecules. Macrocycles appear particular suited for targeting intracellular proteins. It is, however, challenging to develop large macrocycles that simultaneous bind to their targets whilst also showing membrane permeability and sufficient aqueous solubility. Our central goal is to gain understanding of the structure-property relationships of macrocyclic drugs in order to develop the principles necessary for the successful design of new macrocyclic drugs able to treat so far untreatable diseases.

This project is part of the Macrocycle for Drug Discovery (MC4DD) European doctoral network with the three Ph.D. positions being financed by the Marie Skłodowska-Curie Actions (MSCA) of the EU. The successful candidates will work in an international multidisciplinary training network involving 8 academic and 5 industrial partners, including courses and secondments at top-ranking European universities and industry partners.

There are three potential projects and you are asked to specify in your application, which project you are applying for.

Project 1: Understanding macrocycles’ cell permeability by machine learning. The objectives of this subproject are to use machine learning to develop fast and accurate classification and regression models for prediction of macrocycle’s cell permeability, and to use and improve state-of-the-art machine learning technologies for identification of the most important descriptors of the developed models. The successful candidate will receive training in the determination of cell permeability across Caco-2 cell monolayers, in characterizing lipophilicity, polarity and chameleonicity, in the use of PCA and other machine learning methods to select 2D and 3D descriptors for model building, in building theoretical models for cell permeability using various machine learning methods, in the use of data analysis approaches such as PLS, PCA, and clustering to provide insight into the effective set of descriptors governing the output from models, and in determining what extent selected macrocycles behave as molecular chameleons.

Project 2: NMR characterization of macrocycle’s conformational dynamics in solution. The objectives of this project is the development of a solution NMR algorithm for the atomic level description of solution ensembles by combined use of orientational (residual dipolar coupling, scalar coupling) and distance (nuclear Overhauser effect, pseudocontact shift, paramagnetic relaxation enhancement) restrains, the identification of the conformational ensemble of macrocycles, and the development of an NMR method for the determination of macrocycle’s binding mode to their target protein with a higher accuracy than it is achievable today. This project includes training in solution NMR spectroscopy including the determination of NOE build-up rates, residual dipolar couplings, pseudocontact shifts and paramagnetic relaxation rates, in computational conformational searches and combination of spectroscopic and computational data for the identification of solution conformers and their populations.

Project 3: Determination of the solution ensembles of large macrocyclic peptides. The objectives of this project are participation in the synthesis of ~10 large (MW >1000 Da) macrocyclic peptides based on a potent and permeable hit, and in the determination of their cell permeability and target binding, the determination of their solution ensembles in an aqueous environment as well as in a membrane-like, low dielectric environment using advanced solution NMR techniques. The successful candidate will receive training in solid-phase peptide synthesis including chromatographic purification, the determination of cell permeability of across Caco-2 cell monolayers, the determination of NOE build-up rates, scalar couplings, residual dipolar couplings, and pseudocontact shifts, the computational generation of conformational ensembles, and the identification of solution conformers and their populations by combining NMR and computational data.

Duties

The main duties of PhD students are to devote themselves to their research studies, which includes participating in research projects and third cycle courses. The work duties can also include teaching and other departmental duties (not more than 20 % of full time).

Requirements

• To be eligible for doctoral education, a basic higher education equivalent to at least 240 ECTS credits, including at least 60 ECTS credits at second-cycle level, or essentially equivalent competences acquired in some other way, is required. More information about the general requirements can be found here.
• To be admitted to the doctoral education programme in Chemistry with specialization in organic chemistry, 90 ECTS credits in chemistry or courses relevant to the chemistry field, including 40 ECTS credits in organic chemistry at second-cycle level, or essentially equivalent competences acquired in some other way, are required. More information about the subject specific requirements can be found here.
• Very good English proficiency in speech and writing.
• This project requires that you are able to work independently, and that you also have excellent collaborative skills as the project will require that you are able to collaborate with scientists from other universities and industries
• You should have relevant scientific experiences to the project
• Since the position is funded by the Marie Skłodowska Curie Action (MSCA) from EU, there are specific eligibility requirements concerning mobility. Applicants must not have studied or worked in Sweden for more than 12 months during the past 36 months. Please see MSCA’s rules for doctoral networks for details. The doctoral student is also expected to pay extended visits at other partners within the network.

Great emphasis will be placed on personal qualities such as good collaborative skills, motivation and independence, as well as how the applicant through his/her experience and competence is judged to have the abilities necessary to develop within and acquire the doctoral education.

Additional qualifications

• Knowledge and practical experience in machine learning and/or NMR spectroscopy will be seen as strong merits

The ranking of applicants will be based on undergraduate grades, on the undergraduate education profile and on any additional experience of research in areas of relevance for the research project. Such additional experience should be demonstrated and included in your application, e.g. through articles published in international peer-reviewed journals, or by employment at companies or other institutions active in the specific research field. High emphasis will be put on personal qualifications required for the project.

In filling these positions, we aim to recruit the persons who, in a combined evaluation of competence, skills and documented qualifications, are judged most suitable to carry out and develop the project-in-hand and to contributing to a positive development of the department.

Rules governing PhD students are set out in the Higher Education Ordinance chapter 5, §§ 1-7 and in Uppsala University's rules and guidelines.

Rules governing PhD students are set out in the Higher Education Ordinance chapter 5, §§ 1-7 and in Uppsala University's rules and guidelines.

About the employment
The employment is a temporary position according to the Higher Education Ordinance chapter 5 § 7. Scope of employment 100 %. Starting date as agreed. Placement: Uppsala

For further information about the position, please contact:

Mate Erdelyi (e-mail: mate.erdelyi@kemi.uu.se, +46729999166).

Please submit your application by 12 August 2024, UFV-PA 2024/2462.

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