Quantitative structure-activity relationships (QSARs) in inhibitors of various cytochromes P450: The importance of compound lipophilicity

Abstract

The results of extensive quantitative structure-activity relationship (QSAR) analyses on 15 series of cytochrome P450 inhibitors, covering a total of 7 enzymes and 199 compounds, are reported. In general, it is found that lipophilicity represents the most important single factor in describing differences in inhibitory potency towards P450 enzymes. In two instances, this relationship is parabolic in nature but, by and large, the logarithm of inhibitory activity relates linearly with log P, where P is the octanol-water partition coefficient. On occasions, other parameters are involved in the QSAR expressions but there are many examples where either log P or its ionization-corrected equivalent, log D_7.4, are the sole structural descriptors of inhibition. The correlations presented exhibit a range in R value from 0.85 to 0.99, where R is the correlation coefficient, and it is found that R is greater than 0.9 in 80% of the QSARs presented. It is apparent from these findings, therefore, that compound lipophilicity plays a major role in the ability of xenobiotics to inhibit enzymes of the cytochrome P450 superfamily, presumably due to the essentially hydrophobic nature of the active site region.

Keywords::

• Cytochrome P450
• inhibitors
• QSAR
• lipophilicity

Acknowledgements

The financial support of GlaxoSmithKline Research and Development Limited, Merck Sharp & Dohme Limited and the University of Surrey is gratefully acknowledged. We would also like to thank Sandeep Modi (GlaxoSmithKline) for providing us with the CYP1A2 inhibition data.