Ligand-binding properties of human transthyretin

A computational analysis was performed on a selected group of 13 TTR-ligand crystallographic complexes in order to deduce information useful for drug design and discovery. The results obtained can be summarized as follows: (1) the binding site of TTR is a large and very flexible cavity, which is composed of three regions with different chemical features; (2) ligands bind to TTR in forward or reverse modes depending on the conformation adopted by the serine and threonine residues located at the end of the cavity; (3) no relationship could be found between the binding mode of the ligands and their TTR fibrillogenesis inhibitory activity; (4) regardless of the structure, chemical properties or binding mode of the ligand to TTR, there is always a contribution of residues Lys15, Leu17, Ala108, Leu110, Ser117 and Thr119 to ligand binding and finally, (5) the most active compounds are characterised by the presence of at least one halogen atom in the HBP1/HBP1' or HBP3/HBP3' pockets.