GSK
University of Strathclyde

Building and screening of a diverse covalent molecule library for targeted drug discovery

While most medicines work by reversibly binding to proteins in the body involved in disease, covalent drugs are equipped with a key part, called a reactive handle that can form an additional permanent bond to the protein, effectively trapping the drug onto its target. In addition to stronger, longer-lasting therapeutic effects, this strategy has allowed proteins once thought to be “undruggable” to be targeted, making covalent drugs especially valuable for diseases with limited treatment options.

However, despite their vital role in protein binding, only a small pool of these reactive handles is currently being used for the screening of new drug candidates. This may be limiting the development of covalent drugs for disease targets, as different reactive handles have distinct properties that could better suit diverse targets and therapeutic contexts.

To tackle this, Maggie will be creating a library of 5000 highly diverse reactive handle molecules and screening them against a selection of disease-relevant proteins to discover new covalent drug candidates. Instead of relying on time-intensive traditional drug-purification methods, she will use a high-throughput “direct-to-biology” approach, which tests unpurified reaction mixtures directly on proteins. Coupled with a new analytical approach that reduces sample analysis time from 2 minutes to 12 seconds, this will enable her to more rapidly explore exciting reactive handle molecules for development.

Through this work, Maggie aims to unlock new insights into how reactive handles interact with different types of proteins. Her findings have the potential to broaden the reach of drug discovery into territories still considered undruggable, bringing new treatments to patients with unmet medical needs.

Biography

Following the completion of her International Baccalaureate Diploma Programme (IBDP) at Sha Tin College, Maggie received the Hong Kong Scholarship for Excellence Award, a full scholarship that enabled her to pursue her interest in Chemistry through studying an MSci in Chemistry at UCL. She graduated from UCL with a First Class Honours and was included on the Dean’s List, a commendation awarded to the top-scoring 5% of students every year. Her 4th year research project, where she developed methods for site-selective modification of cysteine, deepened her interest in the field and inspired her application for a PhD in Chemical Biology. Maggie is now an Industrial PhD student on the GSK and University of Strathclyde PhD programme.