UC San Diego

The integration of chemical and structural biology with computational tools is critical in drug discovery and for developing novel therapeutics. This dissertation explores the binding of small molecules with protein targets, with a focus on protein-ligand interactions at both structural and functional levels. In part I of this dissertation, I investigate the structural and functional consequences of targeting fascin with benzothiazole amphiphiles (BTA), compounds known to enhance memory and learning in mice and with potential applications in treating neurodegenerative diseases. Chapter 1 summarizes current research on Alzheimer’s disease, the identification of fascin as a target for BTA compounds and its role and function as an actin bundling protein. In Chapter 2, using knockdown studies in primary neurons, I show that fascin expression levels and binding of BTA to fascin are crucial for the phenotypic effect of increased dendritic spine density. In Chapter 3, I use a combination of in silico tools and site-directed mutagenesis experiments to identify a novel binding site for BTA compounds and provide a quantitative understanding of their binding to fascin. In Chapter 4, I provide structural evidence for the binding site of BTA-EG6 to fascin using protein NMR studies. In Chapter 5, I screen other novel BTA analogs and identify a promising lead compound which demonstrates superior binding affinity and functional activity compared to BTA-EG6. In part II of this dissertation, I develop and identify potential drug candidates for Inflammatory Bowel Disease (IBD) by selectively targeting the AMPKβ1 isoform. Chapter 6 discusses the rationale for developing a new therapeutic strategy for IBD via AMPK1 activation, by addressing inflammation and helping to restore and maintain gut barrier integrity. Chapter 7 employs a combination of in silico virtual screening and synthetic chemistry to design and identify a lead compound with better potency and selectivity towards AMPKβ1. Together, these projects represent a comprehensive approach to drug discovery by integrating computational methods, structural biology, and synthetic chemistry to advance our understanding of protein-ligand interactions and their therapeutic potential. The findings contribute to the development of targeted therapies for neurodegenerative diseases and IBD, offering new insights into drug discovery and development.