Diversity Oriented Synthesis of Complex Small Molecules

The basis of modern small molecule medicine is the discovery of molecules which allow scientists to interrogate protein function by inhibition or activation of the protein of interest, often leading to new therapeutic strategies and medicines. One important modern approach to the discovery of new small molecule medicines is fragment-based drug discovery (FBDD), in which small molecules ("fragments") are evaluated in structure-based screens against protein targets of interest in order to identify entities which bind to the protein target. This information is used to build highly potent chemical probes or therapeutic molecules from initial, weakly binding fragments via synthetic manipulation of the initial fragment hit. Although this is a powerful approach, fragment libraries are still limited in their structural diversity, often lacking important features which correspond to improved discovery success, including scaffold diversity (number of different ring systems) fraction of sp3 carbons, and three-dimensional shape. One recent report has identified the lack of synthetic "exit vectors," or functional groups by which the fragments can be derivatised, as a significant bottleneck in the discovery process. vThis same report issued a call for renewed efforts into synthesis of novel fragments which address these issues. This PhD project will address these issues with diversity-oriented synthesis.