title: Generation and validation of rapid computational filters for cyp2d6 and cyp3a4.
abstract: CYP2D6 and CYP3A4 represent two particularly important members of the cytochrome p450 enzyme family due to their involvement in the metabolism of many commercially available drugs. Avoiding potent inhibitory interactions with both of these enzymes is highly desirable in early drug discovery, long before entering clinical trials. Computational prediction of this liability as early as possible is desired. Using a commercially available data set of over 1750 molecules to train computer models that were generated with commercially available software enabled predictions of inhibition for CYP2D6 and CYP3A4, which were compared with empirical data. The results suggest that using a recursive partitioning (tree) technique with augmented atom descriptors enables a statistically significant rank ordering of test-set molecules (Spearman's rho of 0.61 and 0.48 for CYP2D6 and CYP3A4, respectively), which represents an increased rate of identifying the best compounds when compared with the random rate. This approach represents a valuable computational filter in early drug discovery to identify compounds that may have p450 inhibition liabilities prior to molecule synthesis. Such computational filters offer a new approach in which lead optimization in silico can occur with virtual molecules simultaneously tested against multiple enzymes implicated in drug-drug interactions, with a resultant cost savings from a decreased level of molecule synthesis and in vitro screening.
authors.affiliation: Concurrent Pharmaceuticals Inc, Fort Washington, PA 19034, USA. sekins@concurrentpharma.com
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Jennifer
authors.initials: J
authors.lastname: Berbaum
authors.forename: Richard K
authors.initials: RK
authors.lastname: Harrison
mesh_terms: D019295:Computational Biology; D003374:Coumarins / Q000737:chemistry; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D021281:Quantitative Structure-Activity Relationship; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D015203:Reproducibility of Results; D012984:Software
chemical_list: C437963:3-(2-(N,N-diethyl-N-methylammonium)ethyl)-7-methoxy-4-methylcoumarin; C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000644:Quaternary Ammonium Compounds; C084236:7-hydroxy-4-trifluoromethylcoumarin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human