Quantitative Structure-Activity Relationships (QSARs) Within Series of Inhibitors for Mammalian Cytochromes P450 (CYPs)

Abstract

The results of quantitative structure-activity relationship (QSAR) studies on series of F450 inhibitors are reported. Cytochrome F450 families CYP1, CYP2 and CYP51 have been investigated for QSAR analysis, including those of CYP2 subfamilies: CYP2A, CYP2B, CYP2C, CYP2D and CYP2E. The accumulated evidence indicates different structural descriptors being involved, depending on the P450 enzyme concerned, although compound lipophilicity in the form of either logP or logD7.4 appears to represent a common factor in some cases. This is thought to represent desolvation of the P450 active site, although quadratic expressions in lipophilicity tend to suggest that membrane transport is important, especially for CYP2B and CYP2E isoforms. In general, there is close agreement (R = 0.95–0.99) between experimental pKi values and those calculated via QSAR analysis.