P16. Systematic Exploration of 3D Pharmaceutical Space using 3D Bifunctional Building Blocks (CSHP CDT)

There is much interest in 3D heterocyclic scaffolds for medicinal chemistry. Within fragment-based drug discovery, we are developing a synthetic platform to enable the elaboration of 2D fragments into 3D lead compounds, addressing limitations highlighted by industry. This synthetic platform will be less energy and resource-intensive than current approaches because of its modular nature. 

In this project, a set of novel 3D bifunctional building blocks will be designed and synthesised. All of the synthetic routes will be optimised from a sustainability perspective. Systematic coverage of 3D chemical space and 3D vectors will be achieved by an analysis (RDkit) of the conformation and vectors of all possible scaffold isomers from heavy atom count (HAC) 6-10 within our building block design criteria. From this, 20-30 novel 3D building blocks will be selected for synthesis. The building blocks will be (i) used in fragment elaboration and (ii) evaluated as bioisosteres of arenes/heteroarenes. 

To date, we have nine 3D building blocks that are synthetically-enabled for fragment elaboration. The design criteria for the 3D building blocks are: (i) HAC of scaffold = 5-10; (ii) they comprise a N-Boc azetidine, pyrrolidine or piperidine ring; (iii) they contain a cyclopropyl BMIDA group (fixed 3D vectors; synthetically-enabled for cross-coupling). For the 3D vector analysis, the lowest energy conformation of lead-like compounds derived from building blocks will be calculated using RDkit and exit vectors will be determined. 

To develop the fragment elaboration platform, we will target 20-30 new 3D building blocks. We will do this in a systematic manner. Synthetic studies and computational analysis will be carried out and synthesis of a new 3D building block will only be started if it accesses novel 3D vectors that are distinct to our other and commercially available building blocks. Selected potential novel 3D building blocks will contain spiro and fused cyclopropane boronates. Some will be easily accessed based on our developed routes (5-6 steps max.); others will require new synthetic chemistry to access them. Cyclobutyl building blocks will also be studied. All synthetic steps will be optimised to improve sustainability and green credentials. Chromatography-free routes and use of green / sustainable solvents, with earth-abundant metal catalysis will be explored. For the systematic exploration of 3D chemical space, using our design criteria, we will mine Reymond’s GDB-13, a virtual database of 970 million drug-like structures for suitable scaffolds (HAC = 5-10), almost all of which will be completely novel. The 3D building blocks will be used in fragment elaboration and evaluated as bioisosteres of arenes/heteroarenes. The fragment elaboration platform will be less energy and resource-intensive compared to current methods due to its modular nature and small-scale synthesis will address issues of waste generation. 

Supervisory Team:

• Peter O’Brien: peter.obrien@york.ac.uk (York)
• Ed Anderson (Oxford)

Further information 

The EPSRC Centre for Doctoral Training in Chemical Synthesis for a Healthy Planet (CSHP CDT) is a new EPSRC-funded centre focused on training the next generation of synthetic chemists, developing a sustainable, innovative chemistry culture that equips students to address major emerging and future global challenges in Human Health, Energy & Materials, and Food Security. 

We offer a fully-funded four year PhD programme, delivered jointly by the Universities of Oxford and York, comprised of taught courses and a substantive research project. Student cohorts will work together in a 4-month training period at both Oxford and York, before embarking on their main PhD projects. These substantive projects will be industry co-supervised, and based at either the Department of Chemistry in Oxford, or the Green Chemistry Centre of Excellence at York and the associated Department of Chemistry. 

This PhD project will primarily be based at the University of York.  

The first application deadline is 15th November 2024. We will continue to receive applications following this deadline, however some of the projects may be filled following the assessment of the first round of applications. We therefore encourage you to submit your application early to ensure that your first-choice project is available. A full list of CSHP CDT projects on offer for 2025 entry can be found here. 

All project partners recognise the importance of equal participation, progression and success for all. We strive to provide a working, learning, social and living environment that will enable all our staff and students to contribute fully, to flourish and to excel – a place where we can ALL be ourselves. The Department of Chemistry in York holds an Athena SWAN Gold Award, and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel. In particular, we recognise the importance of the equal participation of women at all levels in a subject that has traditionally been male-dominated. We also particularly encourage applications from people who identify as Black, Asian or from a Minority Ethnic background, who are underrepresented in science. 

Eligibility Criteria

You must have, or expect to gain, a minimum UK 2:1 Honours degree or international equivalent in a subject relevant to the proposed PhD project (usually chemistry or chemical engineering, but please get in touch if you think your qualification may be relevant).

Check the entry requirements for your country and the English language requirements.

How to apply:  

Submit an online PhD in Chemistry application.

You will then need to provide the following information: 

• 1000-word personal statement, focusing on your interest and experience in your proposed field of research
• State your 1-2-3 choice of substantive research projects chosen from our list in the section of the form entitled Research Proposals. Please clarify in your personal statement your preferred project.
• A CV (Curriculum vitae)
• Transcripts detailing your university-level qualifications and marks to date
• Two Academic/Professional References: you will be required to submit contact details for 2 referees

The start date of the PhD will be 15 September 2025.

For more details on the application and selection processes, and for answers to general questions (i.e. funding eligibility, project allocation, etc.) please visit our FAQs section.