Systematic discovery of functional allostery for next generation chemical modulators

Allosteric sites provide a fundamentally important mechanism for regulation of protein function, whereby molecular interactions at a remote allosteric site trigger changes in activity at the primary site of protein function - for example an enzyme active site or protein interaction interface. They are highly sought after as sites for selective and unique drug discovery as they are generally less highly conserved across families than the primary site and offer a powerful mechanism to influence otherwise undruggable active sites. A general approach for de novo identification and validation of druggable allosteric molecular pathways would offer game-changing potential for drug discovery against currently intractable targets across all areas of disease.

In this project you will integrate a suite of emerging computational and experimental technologies from our labs to establish the first high-throughput platform for universal discovery, validation, and targeting of functional allosteric sites across the proteome. You will demonstrate proof of concept for your multidisciplinary approach through generation of the first allosteric modulators of human protein translation, deepening our understanding of the rules of life governing functional allostery, as well as underpinning new approaches to anticancer and antiviral therapeutics.

Working across our labs, you will learn and apply new skills and technologies including covalent ligand screening and medicinal chemistry optimisation, in silico modelling and machine learning, CRISPR-Cas gene editing, and molecular cell biology. This project would therefore ideally suit a student with research experience in medicinal chemistry or chemical biology and the ambition to integrate expertise across these areas to create a new drug discovery paradigm.