title: Homology modelling of CYP2A6 based on the CYP2C5 crystallographic template: enzyme-substrate interactions and QSARs for binding affinity and inhibition.
abstract: The results of homology modelling of the human P450 enzyme CYP2A6, based on the CYP2C5 crystallographic template structure are reported. A substantial number of selective substrates of the CYP2A6 enzyme fit the putative active site in a manner that is consistent with their known metabolites. Moreover, the evidence from site-directed mutagenesis experiments is in accordance with the current model, particularly in relation to complementary amino acid contacts within the haem environment. The binding of substrates is rationalized in terms of QSAR analyses and from a consideration of the contributory factors affecting the binding affinity. The latter approach appears to represent a highly correlated (R=0.99) method for estimating the relative strength of enzyme-substrate binding within CYP2A6-selective compounds, albeit within a fairly limited dataset of substrates.
authors.affiliation: School of Biomedical, Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. d.lewis@surrey.ac.uk
authors.forename: D F V
authors.initials: DF
authors.lastname: Lewis
authors.forename: B G
authors.initials: BG
authors.lastname: Lake
authors.forename: M
authors.initials: M
authors.lastname: Dickins
authors.forename: P S
authors.initials: PS
authors.lastname: Goldfarb
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D003461:Crystallography; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D006801:Humans; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D017385:Sequence Homology; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics; D013379:Substrate Specificity; D013698:Templates, Genetic
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C065407:CYP2C5 protein, Oryctolagus cuniculus; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase