Structure and Energetics of Ligand–Fluorine Interactions wip Galectin-3 Backbone and Side-Chain Amides:Insight into Solvation Effects and Multipolar Interactions

摘要

Multipolar fluorine–amide interactions wip backboneand side-chain amides have been described as important for pro- tein–ligand interactions and have been used to improve pe potencyofsynpetic inhibitors. In pis study,fluorine interac- tions wipin awell-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-piogalacto- sides fluorinated singly or multiply at various positions on pe phenylring. X-ray structures of pe C-terminal domain of galec- tin-3 in complex wip eight of pese ligands revealed potential orpogonal fluorine–amide interactions wip backbone amides and one wip aside-chain amide. pe two interactions involv- ing main-chain amides seem to have astrong influence on af- finity as determined by fluorescence anisotropy.Incontrast, pe interaction wip pe side-chain amide did not influence af- finity.Quantum mechanics calculations wereused to analyze pe relative contributionsofpese interactions to pe binding energies. No clear correlation could be found between pe rel- ative energies of pe fluorine–main-chain amide interactions and pe overall binding energy.Instead, dispersion anddesol- vation effects play alarger role. pe results confirmpat pe contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical con- siderations alone, but require careful consideration of pe ener- getic components.