RT Journal Article
SR Electronic
T1 GENERATION AND VALIDATION OF RAPID COMPUTATIONAL FILTERS FOR CYP2D6 AND CYP3A4
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1077
OP 1080
DO 10.1124/dmd.31.9.1077
VO 31
IS 9
A1 Ekins, Sean
A1 Berbaum, Jennifer
A1 Harrison, Richard K.
YR 2003
UL http://dmd.aspetjournals.org/content/31/9/1077.abstract
AB 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 ρ 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. The American Society for Pharmacology and Experimental Therapeutics