Structure and energetics of ligand-fluorine interactions with galectin-3 backbone and side-chain amides - insight into solvation effects and multipolar interactions.

In this study, fluorine interactions within a well-defined binding pocket on galectin-3 are investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at different positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine-amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyse the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine-main chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine-amide interactions to protein-ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.
PMID: 31246331 [PubMed - as supplied by publisher]

Source: ChemMedChem - June 26, 2019 Category: Chemistry Authors: Kumar R, Ignjatović MM, Peterson K, Olsson M, Leffler H, Ryde U, Nilsson UJ, Logan DT Tags: ChemMedChem Source Type: research