title: Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors.
abstract: The purpose of this study was to determine the cytochrome P450 1A2 (CYP1A2) inhibition potencies of structurally diverse compounds to create a comprehensive three-dimensional quantitative structure-activity relationship (3D-QSAR) model of CYP1A2 inhibitors and to use this model to predict the inhibition potencies of an external set of compounds. Fifty-two compounds including naphthalene, lactone and quinoline derivatives were assayed in a 96-well plate format for CYP1A2 inhibition activity using 7-ethoxyresorufin O-dealkylation as the probe reaction. The IC50 values of the tested compounds varied from 2.3 microM to over 40,000 microM. On the basis of this data set, a comparative molecular field analysis (CoMFA) and GRID/GOLPE models were created that yielded novel structural information about the interaction between inhibitory molecules and the CYP1A2 active site. The created CoMFA model was able to accurately predict inhibitory potencies of several structurally unrelated compounds, including selective inhibitors of other cytochrome P450 forms.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kuopio, POB 1627, 70211 Kuopio, Finland. Laura.Korhonen@uku.fi
authors.forename: Laura E
authors.initials: LE
authors.lastname: Korhonen
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto
authors.forename: Niina J
authors.initials: NJ
authors.lastname: Mähönen
authors.forename: Carsten
authors.initials: C
authors.lastname: Wittekindt
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry; D010078:Oxazines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D007783:Lactones; D009281:Naphthalenes; D010078:Oxazines; D011804:Quinolines; C007649:ethoxyresorufin; D019388:Cytochrome P-450 CYP1A2