Quantitative structure-activity relationships within a homologous series of 7-alkoxyresorufins exhibiting activity towards CYP1A and CYP2B enzymes: molecular modelling studies on key members of the resorufin series with CYP2C5-derived models of human CYP1A1, CYP1A2, CYP2B6 and CYP3A4

Abstract

1. The results of quantitative structure–activity relationships (QSARs) within a homologous series of 7-n-alkoxyresorufins are reported. They are consistent with homology modelling of the relevant P450s involved in their metabolism.

2. QSARs were generated for activities involving CYP1A and CYP2B enzymes with structural descriptors relating to compound planarity and other shape parameters, together with certain features of the n-alkoxyresorufin electronic structure, especially electron densities and superdelocalizabilities.

3. A quadratic relationship between compound lipophilicity and binding to CYP2B enzymes was apparent, and which indicated maximal interaction for 7-pentoxyresorufin. Such indications help to explain enzyme selectivity in terms of optimal alkyl chain length for fitting within the relevant active site region.

4. Calculation of the binding affinities for methoxy-, ethoxy-, pentoxy- and benzyloxy-resorufins towards either CYP1A2 or CYP2B6 enzymes, depending on the 7-alkoxyresorufin agree favourably with experimental values obtained from K_m determinations.