Atropisomeric Fragments in Drug Discovery and Probe Compound Development
Lead Research Organisation:
University of Oxford
Abstract
This project falls within the EPSRC Synthetic Organic Chemistry and Chemical Biology & Biological Chemistry research areas.
Fragment-based drug discovery consists of identifying small chemical compounds that weakly bind to a biological target of interest and incorporating these fragments into a larger molecule with the intent of generating an entity that binds the target more strongly. The complexity of a fragment can help to increase the activity and the selectivity of the molecule it is incorporated into, which is valuable in the drug discovery process. Atropisomerism - restricted rotation about a molecular bond - is a phenomenon that can effectively increase the geometrical complexity of a compound, especially when the energy necessary for the bond to rotate (the 'barrier to rotation') is high.
We aim to identify atropisomeric probe compounds that bind strongly and selectively to kinase proteins. The project will involve the development of new methods for the synthesis of atropisomeric compounds and will generate new medicinally relevant fragments with a high barrier to rotation in a selective fashion. Subsequently their barrier to rotation and their biological activity towards various protein targets (including kinases) will be assessed. Methods such as protein soaking and X-ray diffraction crystallography will be useful to determine the interactions of such compounds with target proteins. If successful, the designed probes could be useful in the fields of oncology and inflammation.
Fragment-based drug discovery consists of identifying small chemical compounds that weakly bind to a biological target of interest and incorporating these fragments into a larger molecule with the intent of generating an entity that binds the target more strongly. The complexity of a fragment can help to increase the activity and the selectivity of the molecule it is incorporated into, which is valuable in the drug discovery process. Atropisomerism - restricted rotation about a molecular bond - is a phenomenon that can effectively increase the geometrical complexity of a compound, especially when the energy necessary for the bond to rotate (the 'barrier to rotation') is high.
We aim to identify atropisomeric probe compounds that bind strongly and selectively to kinase proteins. The project will involve the development of new methods for the synthesis of atropisomeric compounds and will generate new medicinally relevant fragments with a high barrier to rotation in a selective fashion. Subsequently their barrier to rotation and their biological activity towards various protein targets (including kinases) will be assessed. Methods such as protein soaking and X-ray diffraction crystallography will be useful to determine the interactions of such compounds with target proteins. If successful, the designed probes could be useful in the fields of oncology and inflammation.