Quantitative structure–activity relationships (QSARs) in CYP3A4 inhibitors: The importance of lipophilic character and hydrogen bonding

Abstract

The results of Quantitative Structure–Activity Relationship (QSAR) analyses on three series of CYP3A4 inhibitors are reported for enzyme inhibition expressed as K_i values. These include a small series of structurally related statins and two larger groupings of structurally diverse compounds, some of which display competitive inhibition of CYP3A4 whereas others act via heme iron ligation. In all cases, however, it is apparent that there are lipophilicity relationships associated with CYP3A4 inhibitory activity in the total of 46 compounds investigated. This is evidenced by linear correlations between inhibition of CYP3A4 and the octanol-water partition coefficient (P value) when expressed logarithmically (ie., log P). In the case of the statins, however, the distribution coefficient (D) at pH 7 is used due to the effect of compound ionization. Conversion of equilibrium constants (ie. K_i and P) to the corresponding free energy changes (ΔG values) facilitates exploration of the likely intermolecular forces of interaction between the inhibitors and the active site region of CYP3A4. In this respect, there appears to be good agreement between QSAR analyses and molecular modelling of the CYP3A4 enzyme itself, and both are consistent with the known mechanisms of inhibition displayed.

Keywords::

• CYP3A4
• inhibition
• partition coefficient
• statins
• QSAR

Acknowledgements

The financial support of GlaxoSmithKline Research and Development Limited, Merck, Sharp & Dohme Limited and the University of Surrey Foundation Fund is gratefully acknowledged by one of us (DFVL).