, Volume 11, Issue 1, pp 43-73

Quantitative structure–activity relationships (QSARs) within the cytochrome P450 system: QSARs describing substrate binding, inhibition and induction of P450s

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Abstract

Quantitative structure-activity relationships (QSARs) within substrates, inducers and inhibitors of cytochromes P450 involved in xenobiotic metabolism are reported, together with QSARs associated with induction, inhibition and metabolic rate. The importance of frontier orbitals and shape descriptors, such as planarity (estimated by the area/depth2 parameter) and rectangularity (estimated by the length/width parameter) is discussed, particularly in the context of the COMPACT system which discriminates between several P450 families associated with the activation and detoxication of xenobiotics. The use of parameters, particularly those derived from homology modelling of mammalian (especially human) P450s that are involved in exogenous metabolism, in generating QSARs for P450 substrates is discussed in the context of explaining differences in the binding affinities of human P450 substrates which are pharmacologically active.