Investigation of enzyme selectivity in the human CYP2C subfamily: homology modelling of CYP2C8, CYP2C9 and CYP2C19 from the CYP2C5 crystallographic template.
Homology modelling of human CYP2C subfamily enzymes, CYP2C8, CYP2C9 and CYP2C19, based on the rabbit CYP2C5 crystal structure template is reported. The relatively high sequence homologies (75-80%) between the rabbit CYP2C5 and human CYP2C subfamily enzymes tend to indicate that the resulting structures should prove adequate models of these major catalysts of human drug metabolism. Selective substrates of all three human CYP2C enzymes are found to fit closely within the putative active sites in a manner which is consistent with site-directed mutagenesis experiments and known positions of substrate metabolism. The specific interactions between substrates and enzymes can be used to rationalize the variation in substrate binding affinity and generate QSAR models for both inhibition and metabolism via CYP2C family enzymes, yielding a generally good agreement with experimental binding data obtained from Km values, with correlation coefficients (R values) of between 0.97 and 0.99 depending on the QSAR equation produced.
Lewis
David F V
DF
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, UK. d.lewis@surrey.ac.uk
Dickins
Maurice
M
Lake
Brian G
BG
Goldfarb
Peter S
PS
D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003461:Crystallography; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8