Selective Galectin-8N Ligands: The Design and Synthesis of Phthalazinone-d-Galactals

Abstract

Ligand selectivity among the highly conserved galectins has been an ever-challenging objective. For galectin-8, a protein prevalent in both pathology and tissue distribution, we report phthalazinone-galactals that show excellent selectivity for the galectin-8N-terminal domain. A dissection of structure-activity relationships of the phthalazinone and an extensive molecular dynamics meta-analysis accompany the discovery of the selective galectin-8N ligands presented here. These selective compounds will facilitate the study of galectin-8 biology and may have pharmaceutical relevance in the wide range of galectin-8 associated pathologies.

Keywords: Drug design; Galectin-8; Inhibitors; Metadynamics; Phthalazinone.