title: Common and Distinct Interactions of Chemical Inhibitors with Cytochrome P450 CYP1A2, CYP2A6 and CYP2B6 Enzymes.
abstract: BACKGROUND
  Tobacco smoking is a leading cause of preventable disease and death globally. Nicotine is the main addictive component in tobacco. Nicotine is eliminated from the body by biotransformation in the liver to inactive metabolites. This reaction is catalyzed by the cytochrome P450 2A6 (CYP2A6) enzyme. Administering chemical inhibitors of CYP2A6 has been shown to slow down the elimination of nicotine with consequent reduction in number of cigarettes smoked. We have systematically developed small molecule CYP2A6 inhibitors with good balance between potency and CYP selectivity.
  
  
  OBJECTIVE
  During this process we have noticed that many potent CYP2A6 inhibitors also inhibit other human liver CYP forms, most notably CYP1A2 and CYP2B6. This study aimed at defining common and distinct features of ligand binding to CYP1A2, CYP2A6 and CYP2B6 active sites.
  
  
  METHODS
  We used our previous chemical inhibitor databases to construct improved 3-dimensional quantitative structureactivity relationship (3D-QSAR) models for CYP1A2, CYP2A6 and CYP2B6.
  
  
  RESULTS
  Combined 3D-QSAR and docking procedures yielded precise information about the common and distinct interactions of inhibitors and the enzyme active sites. Positioning of hydrogen bond donor/acceptor atoms and the shape and volume of the compound defined the potency and specificity of inhibition. A novel potent and selective CYP1A2 inhibitor was found.
  
  
  CONCLUSIONS
  This in silico approach will provide a means for very rapid and high throughput prediction of cross-inhibition of these three CYP enzymes.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Box 1627, 70211 Kuopio, Finland.. hannu.raunio@uef.fi.
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto-Rilla
mesh_terms: D020134:Catalytic Domain; D017076:Computer-Aided Design; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065637:Cytochrome P-450 CYP2A6 / Q000737:chemistry / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6 / Q000737:chemistry / Q000378:metabolism*; D065686:Cytochrome P-450 CYP2B6 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065686:Cytochrome P-450 CYP2B6 Inhibitors; D008024:Ligands; C504573:CYP1A2 protein, human; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6