Structural requirements for binding of nonsteroidal anti-inflammatory drugs to human serum albumin.

The binding of representative chemical classes of nonsteroidal anti-inflammatory drugs (NSAIDs) to human serum albumin (HSA) was investigated by equilibrium dialysis. Warfarin enantiomers were used as specific markers in displacement studies. Data were analyzed by a computerized nonlinear least squares approach designed for binding of small ligands to macromolecules at equilibrium. The binding data indicated comparable affinities to the primary site by the warfarin enantiomers, phenylbutazone, and meclofenamate sodium. Naproxen, sulindac, and zomepirac showed lower affinity by one order of magnitude. The displacement data revealed stereoselectivity. The R(+) isomer was displaced to a significantly greater extent than the S(-) isomer by meclofenamate sodium, while the reverse was observed for phenylbutazone. Naproxen displaced both isomers to the same extent. No significant displacement of either isomer was seen with sulindac or zomepirac. Examination of the chemical structures of the high affinity compounds indicated the common feature of a hydrophobic area bearing a widely delocalized negative charge. Hydrophobic binding of these compounds to HSA at the warfarin site is possibly stabilized by the attraction of the delocalized negative charge to the basic lysine and arginine residues adjoining the lone tryptophan.