Small-Molecule Galectin Ligands: Structure-Based Optimisation of Affinity and SelectivityVan Klaveren, Sjors (Avtor) Tomašič, Tihomir (Mentor) Nilsson, Ulf J. (Komentor) Galectinsligandsinhibitorsdrug discoverymolecular dynamics simulationsvirtual screeningdocking studiesstructure-activity relationshipX-ray crystallography.In the body, all cell surfaces are covered with glycans, and many regulatory components have carbohydrates attached to them, which can aid in their function. Galectins are a family of proteins which can bind to specific glycans and oligosaccharides and cross-link them to influence a wide range of cellular processes. The members of the galectin family are structurally similar and can be involved in the same processes. Inside the cell, galectins have been observed assisting in the detection of exposed glycans on damaged intracellular vesicles, initiating autophagy which helps to clear out damaged cells and bacterial infections. Some galectins have a role in promoting angiogenesis and lymphangiogenesis. This is associated with the repair of damaged tissue and with the growth of tumours. Studies have also implicated galectins in autoimmune disorders and neurodegenerative diseases. The research in this doctoral dissertation focused on the discovery and development of selective, high-affinity ligands for several galectins, with a special focus on galectin-8. Several structurally diverse libraries of compounds were synthesised as part of ligand-based and structure-based approaches. From these libraries, several novel hits for galectin-1, -3, and -8N were discovered and structure–activity relationships identified. These hits were optimised to produce galectin ligands with sub-micromolar affinities and analogues with almost complete selectivity for galectin-8N over all other tested galectins. Such highly selective compounds may help to study the biological roles of galectins and the pathologies in which they are involved. This may also, in turn, lead to galectin-8N inhibitors with a pharmaceutical potential.20242024-04-06 07:15:07Doktorsko delo/naloga155554sl