Download the full description of this project: ESR6: FBLD experimental methods
FBLD technologies are continuously being improved to capture new opportunities. This project will study the use of biosensor-‐based technologies to study ligand-‐protein binding events.
Develop biosensor-‐based assays for epigenetic target proteins interacting with histones. 2. Screen proprietary FragNet fragment libraries against selected target proteins. 3. Characterize fragment hits using same biosensor-‐based methods and orthogonal assays. 4. Use experimental data in computer-‐assisted drug design. 5. Optimise fragment hits.
New biosensor instruments and methods will be used for development of highly sensitive and informative assays suitable for epigenetic targets that interact with and modify histone proteins. The methods will address the challenges associated with detection of weakly interacting small molecules (fragments) and will be focused on distinguishing ligands with a functional effect from binders that simply interact with the protein. The assays will be designed for direct or indirect detection of fragments that can directly block interactions with the protein substrate/binding partner or that have enough binding energy to induce the required conformational changes for allosteric inhibition of protein-‐protein interactions. Biophysical methods will be developed for identifying ligand binding sites, i.e., binding to the protein-‐protein interaction surface (corresponding to the active site for non-‐enzyme targets) or an allosteric site. Computational studies of hits will be performed as a complement to experimental studies, with a focus on identifying potential binding sites, binding modes and interaction features of weakly interacting ligands. The design of any new ligands can be supported by computer-‐aided drug design studies and synthesis will be performed in collaboration with other ESRs.
Required diploma: MSc degree in Biochemistry, Biophysics or related Molecular Life Science degree. Required expertise: Experience in biochemical and/or biophysical characterization of proteins. The candidate has a strong background in biochemistry or biophysics, and has experience in variety of methods for producing proteins and characterizing their structural and functional properties. Recommended expertise: Use of advanced biophysical instruments and development of new biochemical and biophysical assays. An interest in computer-‐aided drug design and mathematical modelling and statistical analysis of biochemical data would be an advantage. The candidate needs to be able to discuss and develop methods in collaboration with other ESRs.
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