QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS BASED ON COMPUTER CALCULATED PARAMETERS FOR THE OVERALL RATE OF GLUTATHIONE-S-TRANSFERASE CATALYZED CONJUGATION OF A SERIES OF FLUORONITROBENZENES

The present study describes quantitative structure-activity relationships (QSAR's) for the overall rate of conjugation of a series of fluoronitrobenzenes catalyzed by cytosolic glutathione S-transferases based on experimental data and outcomes of computer calculations. The natural logarithm of the rate of conjugation of the series of fluoronitrobenzenes correlates (r = -0.986) with the calculated energy (E) of their lowest unoccupied molecular orbital (LUMO) and also (r = -0.987) with the relative heat of formation (Delta Delta HF) for formation of the Meisenheimer complex of the fluoronitrobenzenes with a MeS(-) model nucleophile. In addition, the paper describes QSAR's for the chemical reaction of glutathione with the fluorinated nitrobenzenes both at pH 7.6 and at pH 9.9. These QSAR's are parallel to the one obtained for the enzyme catalyzed conversions. This indicates that in the overall reaction (both chemical and enzyme catalyzed) the interaction between the thiolate anion of glutathione and the fluoronitrobenzene leading to the Meisenheimer reaction intermediate is the rate-limiting step in overall conversion of these substrates. The parallel QSAR's of the chemical and enzymatic reaction also indicate that in the enzymatic reaction chemical reactivity parameters determine the overall outcome of catalysis and, in addition, that the chemical and enzymatic reactions proceed through a similar reaction pathway with comparable reaction intermediates. Additional results of the present study demonstrate that the regioselectivity of the glutathione conjugation cannot be explained on the basis of calculated characteristics of the LUMO of the fluoronitrobenzenes or the Delta Delta HF for the formation of their Meisenheimer reaction complex. Taken together, the results of the present study demonstrate that the number of fluorine substituents in the fluoronitrobenzenes influences the kinetic characteristics, apparent K-m and V-max, for their conversion by the glutathione S-transferases in a way that can be described by quantitative structure-activity relationships (QSAR's) which are based on outcomes of computer calculations. The use of molecular orbital computer calculations for characterizing a QSAR for the rate of conversion of a series of substrates by glutathione S-transferases provides another approach than the description of QSAR's on the basis of Hammett substituent constants, which is the approach mostly described up to now for the glutathione S-transferase catalyzed reactions.