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Modular Synthetic Platform for the Optimisation of Fragment Hits Using Bifunctional 3-D Building Blocks: Application to Covid-19 Proteins


Department of Chemistry

York United Kingdom Organic Chemistry Pharmaceutical Chemistry Synthetic Chemistry

About the Project

Background

Fragment-based methods are established for the identification of lead compounds in drug discovery.[1] Fragments are small molecules (molecular weight ~150-300) which bind weakly to proteins. However, especially with X-ray crystal structures of protein-fragment complexes, the elaboration of a fragment to designed lead compounds (MW ~400-500) which are strong protein binders, can be achieved. The synthetic chemistry needed to optimise a fragment hit to a lead compound remains a bottleneck in fragment-based drug discovery, as highlighted by Astex recently.[2] This is especially true when optimising along 3-D vectors. As a result, in this project, we will develop a modular synthetic platform that will enable fragments in current libraries[3] to be elaborated into 3-D lead compounds with functionality in defined 3-D vectors.

Objectives

1. Design and synthesis of cyclopropyl bifunctional 3-D building blocks

2. Development of synthetic chemistry for attachment of fragments and further elaboration to lead-like compounds

3. Development of hit compounds against covid-19 protein targets

Experimental Approach

Initially, a set of cyclopropyl bifunctional 3-D building blocks will be designed to include common functionality for further elaboration. The 3-D building blocks will comprise a protected amine and a cross-coupling handle on different 3-D bicyclic, fused or spirocyclic scaffolds. The 3-D vectors provided by each novel, designed 3-D building block will be assessed using a computational tool to ensure that they provide distinct 3-D vectors compared to other building blocks. Then, each of the 3-D building blocks will be synthesised on a multi-gram scale, addressing issues of diastereo- and enantioselectivity. Next, it will be necessary to demonstrate that robust and orthogonal synthetic chemistry can be used to attach the 3-D building blocks to common fragments.[3] It will also be necessary to explore methodology for further functionalisation of the fragment-building block hybrid to explore lead-like space. Finally, through the collaboration with researchers at Oxford, the elaboration of fragment hits against covid-19 proteins to lead-like compounds will be also be explored.[4,5]

Novelty

The concept of developing a synthetic platform to facilitate the elaboration of fragments to lead-like compounds is novel. It builds effectively on several hot topics in the synthesis and fragment medicinal chemistry arenas. This project forms part of Peter O’Brien’s Royal Society Industry Fellowship with AstraZeneca.

Training

This project will provide state-of-the-art training in modern synthetic methodology and medicinal chemistry. The graduating PhD student will be fully equipped for a future career in the pharmaceutical industry. All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/training/idtc/

The Department of Chemistry 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: https://www.york.ac.uk/chemistry/ed/.

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

For more information about the project, click on the supervisor’s name above to email the supervisor. For more information about the application process or funding, please click on email institution


Funding Notes

This project is available to students from any country who can fund their own studies. The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website

References

1. D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke and H. Jhoti, Nat Rev Drug Discov, 2016, 15, 605.
2. C. W. Murray and D. C. Rees, Angew. Chem. Int. Ed., 2016, 55, 488.
3. M. J. Waring et al. J. Med. Chem. 2019, 62, 3741.
4. https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html
5. https://www.diamond.ac.uk/covid-19/for-scientists/NSP3-macrodomain-structure-and-XChem.html

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