Exploring Chemical Space with Boron

Abstract

Chemical space, in its vastness, affords nearly unlimited opportunities to develop novel molecules. However, to explore these uncharted regions of chemical space, there is a need for structurally unique molecules with increased complexity and balanced chemical properties. This thesis, in part, explores novel approaches to sampling chemical space through the development of boron-based molecular entities, addressing gaps that traditional organic chemistry alone cannot fill. In Chapter 2, the need for potent and selective inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in immunotherapy and cancer immunity escape was addressed. We successfully enhanced inhibitory potency of small molecules by incorporating unique boron functionalities into two distinct organic scaffolds with inhibition of the IDO1 enzyme increased by up to ca. 80% compared with organic analogues. Next, Chapter 3 expanded and screened a world-first boron fragment library against IDO1, identifying multiple fragments displaying micromolar inhibition and excellent reversible binding to the enzyme. This result represents a significant advancement over the use of traditional organic FBDD fragment libraries in the identification of 'hit' fragments, and which typically show only millimolar binding affinities at the earliest stages of the drug discovery journey. Our findings suggest that key structural features of important boron motifs can enhance fragment binding and inhibition over traditional organic fragments, paving the way for further structural optimisation and fragment linking strategies. Overall, this work underscores the potential of boron-based chemistry in expanding drug discovery and materials science. By navigating chemical space with innovative boron scaffolds, we have demonstrated new opportunities in enzyme inhibition, FBDD, and ligand design in coordination chemistry.