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-act ivity relationships (QSARS) between these structural parameters and th e rates of metabolism of the alkoxyresorufins in hepatic microsomes fr om the 3-methylcholanthrene (MC)-, and phenobarbital (PB)-pretreated m ouse, and the beta-naphthoflavone (PNF)-pretreated rat have been estab lished. 3. The most significant single relationship is between beta NF -induction of cytochrome P4501 (CYP1A) and the total nucleophilic supe rdelocalizability (Sigma S-N) 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 hydrop hobic substituent constant (pi). 5. These findings indicate that the r ates 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 nucleophi lic species. 6. A different set of parameters correlated with CYP2B ac tivity, 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 s tudies of the alkoxyresorufins with their affinity-specific cytochrome s P450, namely, methoxy- with CYP1A2; ethoxy- with CYP1A1; pentoxy- wi th CYP2B1; and benzyloxy- with CYP3A, have also been undertaken to sho w the specific interactions of the alkoxyresorufins with the binding s ites of the individual P450s.