title: Lipophilicity relationships in inhibitors of CYP2C9 and CYP2C19 enzymes.
abstract: Quantitative structure-activity relationships (QSARs) within a series of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) inhibitors are reported. In particular, it is noted that compound lipophilicity, in the form of log P values (where P is the octanol/water partition coefficient), is an important factor in explaining the variation in inhibitory potency within these series of compounds, many of which also act as substrates for the respective enzymes. In addition, there is a role for hydrogen bonding and pi-pi stacking interactions within the P450 active site which represent secondary factors in the binding processes of these compounds.
authors.affiliation: School of Biomedical and Molecular Sciences University of Surrey, Guildford, Surrey, GU2 XH, 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: Yuko
authors.initials: Y
authors.lastname: Ito
authors.forename: Maurice
authors.initials: M
authors.lastname: Dickins
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000737:chemistry*; D000442:Octanols / Q000737:chemistry; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D000442:Octanols; D014867:Water; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19