Design and Synthesis of Trifunctionalised 3-D Stereoprobes for Drug Discovery

This PhD project, supervised by Professor P O'Brien at the University of York, focuses on the design and synthesis of trifunctionalised 3-D stereoprobes for drug discovery. The O’Brien group is internationally recognised for its research in synthetic organic chemistry, particularly the development of 3-D fragments and building blocks for pharmaceutical applications. Building on recent advances in the use of stereochemically defined reactive fragments (stereoprobes) to expand the binding potential of the human proteome, this project aims to create fully synthetically-enabled trifunctionalised 3-D stereoprobes for direct-to-biology drug discovery screening. A key innovation is the use of all stereoisomers (diastereomers and enantiomers) to explore ligand-protein binding interactions, with the stereoprobes typically featuring saturated nitrogen heterocyclic cores such as pyrrolidine, piperidine, or piperazine, and a heteroaryl fragment. The project will also introduce a third functional group as a synthetic handle, enabling rapid library generation and expanding the chemical space for screening. The research objectives include designing and synthesising trifunctional 3-D stereoprobes with defined stereochemistry, developing direct-to-biology-compatible amide formation, sp3-sp2 Suzuki-Miyaura cross-coupling, and acrylamide formation, and demonstrating direct-to-biology screening of the new compounds. The experimental approach involves advanced synthetic organic chemistry techniques, purification, and NMR characterisation, with a strong emphasis on asymmetric synthesis and reaction optimisation. The project is multidisciplinary, integrating medicinal chemistry and offering opportunities for collaboration with the pharmaceutical industry. Training will be provided in scientific, transferable, and employability skills, with access to a vibrant research environment, weekly group meetings, and funding for conferences and external training. The Department of Chemistry at York is committed to equality, diversity, and widening participation, holding an Athena SWAN Gold Award and supporting under-represented groups through initiatives like the YCEDE project. Applicants should have or expect to achieve at least a UK upper second class degree in Chemistry or a related subject, with international applicants required to meet country-specific and English language requirements. Funding is available through the Department of Chemistry, EPSRC, or the Chemistry Wild Fund, covering tuition fees, a tax-free stipend (£20,780 for 2025/26), and research costs for 3 or 3.5 years, depending on the funder. The application deadline is 6 January 2026, with shortlisted candidates invited to panel interviews in February. This project offers a unique opportunity to contribute to cutting-edge drug discovery research and develop a broad skill set in synthetic and medicinal chemistry.