Quantitative Structure-Activity Relationships (QSARs) Within Substrates of Human Cytochromes P450 Involved in Drug Metabolism

The results of quantitative structure-activity relationship (QSAR) analyses are reported for structurally diverse series of chemicals which act as substrates or inhibitors for human hepatic microsomal cytochromes P450 (CYP). In particular, this study focuses on the major catalysts of drug metabolism in man, namely CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. It is found that good correlations (with correlation coefficients ranging from R = 0.94 to 0.99) with P450 binding affinity (Km and K(D)) or competitive inhibition (Ki) values are obtained in each case, especially when consideration of hydrogen bonding parameters are included in the QSAR analysis, together with the number of pi-pi stacking interactions.

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