RT Journal Article SR Electronic T1 Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2195 OP 2203 DO 10.1124/dmd.110.034645 VO 38 IS 12 A1 Abhinav Nath A1 Michael A. Zientek A1 Benjamin J. Burke A1 Ying Jiang A1 William M. Atkins YR 2010 UL http://dmd.aspetjournals.org/content/38/12/2195.abstract AB Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by small-molecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors.