Design, Synthesis and Evaluation of a Shape-Diverse Fragment Library

This thesis describes the development of a fragment library in order to identify the value of shape-diverse molecules in their ability to target novel areas of shape-space.
Chapter 1 introduces known approaches to ligand discovery as well as the concept of chemical space and molecular shape diversity. Chapter 2 describes the computational tools and protocols used to identify fragments of interest from both commercial and Leeds libraries, that fulfil the criteria of maximum coverage of reference shapes as well as high shape-diversity. The synthesis of fragments based on Leeds chemistry is described in Chapter 3, focusing on four key chemistries established within the Nelson group, as well as the reselection of molecules to overcome synthetic challenges. Chapter 4 describes the screen of the library of fragments using high-throughput X-ray crystallography, as well as the development of a novel fragment hit against Aurora A kinase. Overall my fragment library was successful in its ability to investigate unexplored shape-space and presented valuable hits against a useful target.