title: Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates: comparative analysis, molecular docking, bioactivation and toxicological implications.
abstract: Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme responsible for metabolizing approximately 25% of all drugs. CYP2D6 is highly expressed in the brain and plays a role as the major CYP in the metabolism of numerous brain-penetrant drugs, including antipsychotics and antidepressants. CYP2D6 activity and inhibition have been associated with numerous undesirable effects in patients, such as bioactivation, drug-associated suicidality and prolongation of the QTc interval. Several in silico tools have been developed in recent years to assist safety assessment scientists in predicting the structural identity of CYP2D6-derived metabolites. The first goal of this study was to perform a comparative evaluation on the ability of four commonly used in silico tools (MetaSite, StarDrop, SMARTCyp and RS-WebPredictor) to correctly predict the CYP2D6-derived site of metabolism (SOM) for 141 compounds, including 10 derived from the Genentech small molecule library. The second goal was to evaluate if a bioactivation prediction model, based on an indicator of chemical reactivity (ELUMO-EHOMO) and electrostatic potential, could correctly predict five representative compounds known to be bioactivated by CYP2D6. Such a model would be of great utility in safety assessment since unforeseen toxicities of CYP2D6 substrates may in part be due to bioactivation mechanisms. The third and final goal was to investigate whether molecular docking, using the crystal structure of human CYP2D6, had the potential to compliment or improve the results obtained from the four SOM in silico programs.
authors.affiliation: a Department of Safety Assessment .
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Ford
authors.affiliation: b Department of Nonclinical Biostatistics and.
authors.forename: Gregory
authors.initials: G
authors.lastname: Ryslik
authors.affiliation: c Department of Drug Metabolism and Pharmacokinetics , Genentech, Inc. , South San Francisco , CA , USA , and.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Sodhi
authors.affiliation: d Department of Drug Metabolism and Pharmacokinetics , Anacor Pharmaceuticals, Inc. , Palo Alto , CA , USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.affiliation: a Department of Safety Assessment .
authors.forename: Dolo
authors.initials: D
authors.lastname: Diaz
authors.affiliation: a Department of Safety Assessment .
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
authors.affiliation: a Department of Safety Assessment .
authors.forename: Melisa
authors.initials: M
authors.lastname: Masuda
mesh_terms: D065767:Activation, Metabolic; D001665:Binding Sites; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D062105:Molecular Docking Simulation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D018570:Risk Assessment; D012307:Risk Factors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D019389:Cytochrome P-450 CYP2D6
keywords: Bioactivation; CYP2D6; in silico prediction; neurotoxicity; site of metabolism