The uridine diphosphate glucuronosyltransferases: quantitative structure-activity relationships for hydroxyl...

Quantitative structure-activity relationships (QSARs), which relate the glucuronidation of hydroxyl polychlorinated biphenyls (OH-PCBs)-catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs)-to their physicochemical properties and molecular structural parameters, can be used to predict the rate constants and interpret the mechanism of glucuronidation. In this study, QSARs have been developed that use 23 semi-empirical calculated quantum chemical descriptors to predict the logarithms of the constants 1/K(m) and V(max), related to enzyme kinetics. A partial least squares regression method was used to select the optimal set of descriptors to minimize the multicollinearity between the descriptors, as well as to maximize the cross-validated coefficient (Q(2) (cum)) values. The key descriptors affecting log(1/K(m)) were E(lumo)- E(homo) (the energy gap between the lowest unoccupied molecular orbital and the highest occupied molecular orbital) and q(C) (-) (the largest negative net atomic charge on a carbon atom), while the key descriptors affecting logV(max) were the polarizability alpha, the Connolly solvent-excluded volume (CSEV), and logP (the logarithm of the partition coefficient for octanol/water). From the results obtained it can be concluded that hydrophobic and electronic aspects of OH-PCBs are important in the glucuronidation of OH-PCBs.