Molecular orbital-generated QSARs in a homologous series of alkoxyresorufins and studies of their interactive docking with P450s.

1. Molecular and electronic structural parameters have been determined, by molecular orbital (MO) calculations, for a homologous series of 8 alkoxyresorufins (methoxy- to octoxy-). 2. Quantitative structure-activity relationships (QSARs) between these structural parameters and the rates of metabolism of the alkoxyresorufins in hepatic microsomes from the 3-methylcholanthrene (MC)-, and phenobarbital (PB)-pretreated mouse, and the beta-naphthoflavone (beta NF)-pretreated rat have been established. 3. The most significant single relationship is between beta NF-induction of cytochrome P4501 (CYP1A) and the total nucleophilic superdelocalizability (sigma SN) for the eight compounds in the series. 4. For double regressions, the electronic charge on the alkoxy oxygen, Q(O), or alpha-carbon Q(C), is important when combined with the hydrophobic substituent constant (pi). 5. These findings indicate that the rates of metabolism of these alkoxyresorufins are dependent upon their ability to cross cellular membranes, to fit the relevant CYP1A binding site, and on their ability to accept electrons from a donor nucleophilic species. 6. A different set of parameters correlated with CYP2B activity, namely, parameters of overall shape, which indicates that the way in which the alkoxyresorufins fit the CYP2B site, determines their differences in specificity. 7. Computer graphic interactive docking studies of the alkoxyresorufins with their affinity-specific cytochromes P450, namely, methoxy- with CYP1A2; ethoxy- with CYP1A1; pentoxy- with CYP2B1; and benzyloxy- with CYP3A, have also been undertaken to show the specific interactions of the alkoxyresorufins with the binding sites of the individual P450s.