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Modular Synthetic Platform for the Optimisation of Fragment Hits Using Bifunctional 3-D Building Blocks


   Department of Chemistry

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Modular Synthetic Platform for the Optimisation of Fragment Hits Using Bifunctional 3-D Building Blocks

Supervisor: Peter O’Brien

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 and cyclobutyl 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 different proteins to include SARS-CoV-2 proteins

Experimental Approach

Initially, a set of cyclopropyl and cyclobutyl 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 collaborations, the elaboration of fragment hits against different proteins (including those in SARS-CoV-2) to lead-like compounds will also be explored.

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.

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/cdts/    

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/ .


Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to new students who will pay tuition fees at the overseas rate. Scholarships are competitive and awarded based on academic ability and financial need. For further information see: View Website

References

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.

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