title: 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 Ki 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. Ki and P) to the corresponding free energy changes (deltaG 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.
authors.affiliation: School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. d.lewis@surrey.ac.uk
authors.forename: David F V
authors.initials: DF
authors.lastname: Lewis
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lake
authors.forename: Maurice
authors.initials: M
authors.lastname: Dickins
mesh_terms: D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008055:Lipids; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human