title: Molecular modelling of CYP2B6 based on homology with the CYP2C5 crystal structure: analysis of enzyme-substrate interactions.
abstract: The results of homology modelling of CYP2B6 based on the CYP2C5 crystal structure is described in terms of substrates and inhibitors binding within the putative active site. In general these results are in agreement with currently available evidence from substrate metabolism, mode of inhibitor action and site-directed mutagenesis experiments within the CYP2B subfamily of enzymes. Consequently, the model based on the CYP2C5 template represents an advance on those models produced from bacterial P450s, such as CYP101 and CYP102. Quantitative Structure-Activity Relationships (QSARs) for substrates binding to CYP2B6 indicate a key role for hydrogen bonding, and lipophilic character, as determined by the log P parameter (where P is the octanol/water partition coefficient), is also of importance for explaining the variation in experimental binding affinity for CYP2B6 substrates. It is possible to estimate the binding energies for typical CYP2B6 substrates based on their properties and interactions with the enzyme, which show good concordance with experimental data in the form of apparent Km values.
authors.affiliation: School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, 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
authors.forename: Peter S
authors.initials: PS
authors.lastname: Goldfarb
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics; D003460:Crystallization; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008958:Models, Molecular; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C065407:CYP2C5 protein, Oryctolagus cuniculus; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; D010089:Oxidoreductases, N-Demethylating