This proposal aims to exploit diversity-oriented synthesis in order to lay the scientific and technological foundations for the development of enzyme inhibition by protein-protein interaction (PPI) modulation as a tool for chemical biology and molecular therapeutics. We will deploy diversity-oriented synthesis lead discovery to explore concepts for PPI modulation in important enzyme families. This work will yield new chemical entities with a spectrum of properties directed against candidate macromolecular interactions important in the regulation of enzymes that mediate key biological pathways. The proposed work has the potential to transform current approaches to drug discovery, and to radically extend the repertoire of tools available for chemical biology. It will help to address the problem of identifying small-molecule inhibitors of PPIs, widely accepted to be of major fundamental and practical significance to biomedical science.
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