title: Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9.
abstract: Several laboratories have demonstrated that activation of drug metabolism by P450s may occur via a mechanism that resembles allosterism from an enzyme kinetic standpoint. Because the effector drug binding site may be located in the same P450 binding pocket where the drug substrate is located, the ability to find and characterize novel effectors (aka heteroactivators) will prove to be important in probing the mechanism of activation. We have used analogues of the prototypical CYP2C9 heteroactivator dapsone to validate a simple docking method that can be used to predict heteroactivators based on ligand binding location in a P450 crystal structure. As proof of concept for the described docking method, a protocol was developed to discover potential heteroactivators from a virtual chemical library through efficient sorting of >40,000 compounds. One of the top-scoring compounds identified was verified to be a CYP2C9 heteroactivator in vitro, and it possessed activity similar to dapsone.
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gannett
authors.forename: Robyn
authors.initials: R
authors.lastname: Ayscue
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Tracy
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D065729:Cytochrome P-450 CYP2C9; D003622:Dapsone / Q000737:chemistry; D016208:Databases, Factual; D020536:Enzyme Activators / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry; D005480:Flurbiprofen / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005480:Flurbiprofen; D003622:Dapsone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D009251:NADPH-Ferrihemoprotein Reductase