Cross-correlated F-19 relaxation measurements for the study of fluorinatedligand-receptor interactions

Fluorine is often used in drug-design efforts to enhance the pharmacokineti c properties of biologically active compounds. Additionally fluorine nuclei (F-19) have properties that are well suited to current pharmaceutical NMR screening programs. Together, these considerations have motivated our inter est in the utility of fluorine relaxation parameters to study ligand-recept or interactions. Here, we investigate the potential for cross-correlated re laxation effects between the F-19 anisotropic chemical-shift and F-19-H-1 d ipole-dipole relaxation mechanisms to help pinpoint and quantify exchange p rocesses. Methods are proposed and demonstrated in which the magnitude rati o of the transverse cross-correlation rate constant eta (xy) and the fluori ne transverse relaxation rate constant, R-2, help estimate the exchange rat e constant for ligand-binding equilibria. These exchange rate constants pro vide estimates of the ligand dissociation rate constants k(off) and can thu s provide a means for rank-ordering the binding affinities of ligands ident ified in pharmaceutical screens. (C) 2001 Academic Press.