Liu, Li-Kai2016-10-252016-10-252015-06https://hdl.handle.net/11299/182799University of Minnesota Ph.D. dissertation. June 2015. Major: Medicinal Chemistry. Advisor: Barry Finzel. 1 computer file (PDF); xi, 215 pages.Selective inhibitors of hyaluronan (HA) binding to the cell surface receptor CD44 will have value as probes of CD44-mediated signaling, and have potential as therapeutic agents in chronic inflammation, cardiovascular disease and cancer. Using biophysical binding assays, fragment screening, and crystallographic characterization of complexes with the CD44 HA binding domain, we have discovered an inducible pocket adjacent to the HA binding groove into which small molecules may bind. Fragment combination and iterations of structure-driven design has led to identification of a series of 1,2,3,4-tetrahydroisoquinolines as the first non-glycosidic inhibitors of the CD44-HA interaction. The affinity of these molecules for the CD44 HA binding domain parallels their ability to interfere with CD44 binding to polymeric HA in vitro. X-ray crystallographic complexes with lead compounds are described and compared to a new complex with a short HA tetrasaccharide, in order to establish the tetrahydroisoquinoline pharmacophore as an attractive starting point for lead optimization.enBiophysical assayDrug discoveryfragment screeningStructural-based designThesis or Dissertation