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. 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. 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 to be elaborated into 3-D lead compounds with functionality in defined 3-D vectors.
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
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. 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.
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 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/
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