title: Quantifying and predicting the promiscuity and isoform specificity of small-molecule cytochrome P450 inhibitors.
abstract: 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.
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, P.O. Box 208114, New Haven, CT 06520-8114, USA. abhinav.nath@yale.edu
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nath
authors.forename: Michael A
authors.initials: MA
authors.lastname: Zientek
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: William M
authors.initials: WM
authors.lastname: Atkins
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D019277:Entropy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D016018:Least-Squares Analysis
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes