Fluorine-protein interactions and ¹⁹F NMR isotropic chemical shifts: An empirical correlation with implications for drug design

Abstract

An empirical correlation between the fluorine isotropic chemical shifts, measured by ¹⁹F NMR spectroscopy, and the type of fluorine-protein interactions observed in crystal structures is presented. The CF, CF₂, and CF₃ groups present in fluorinated ligands found in the Protein Data Bank were classified according to their ¹⁹F NMR chemical shifts and their close intermolecular contacts with the protein atoms. Shielded fluorine atoms, i.e., those with increased electron density, are observed primarily in close contact to hydrogen bond donors within the protein structure, suggesting the possibility of intermolecular hydrogen bond formation. Deshielded fluorines are predominantly found in close contact with hydrophobic side chains and with the carbon of carbonyl groups of the protein backbone. Correlation between the ¹⁹F NMR chemical shift and hydrogen bond distance, both derived experimentally and computed through quantum chemical methods, is also presented. The proposed "rule of shielding" provides some insight into and guidelines for the judicious selection of appropriate fluorinated moieties to be inserted into a molecule for making the most favorable interactions with the receptor.