title: QSAR modeling of in vitro inhibition of cytochrome P450 3A4.
abstract: We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.
authors.affiliation: Cerep, 15318 NE 95th Street, Redmond, Washington 98052, USA. bmao@cerep.com
authors.forename: Boryeu
authors.initials: B
authors.lastname: Mao
authors.forename: Rafael
authors.initials: R
authors.lastname: Gozalbes
authors.forename: Frédérique
authors.initials: F
authors.lastname: Barbosa
authors.forename: Jacques
authors.initials: J
authors.lastname: Migeon
authors.forename: Sandra
authors.initials: S
authors.lastname: Merrick
authors.forename: Kelly
authors.initials: K
authors.lastname: Kamm
authors.forename: Eric
authors.initials: E
authors.lastname: Wong
authors.forename: Chester
authors.initials: C
authors.lastname: Costales
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froloff
mesh_terms: D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human