title: In Silico Predictions of Drug - Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition - a Comparative Study of Virtual Screening Performance.
abstract: The cytochrome P450 (CYP) superfamily represents the major enzyme class responsible for the metabolism of exogenous compounds. Investigation of clearance pathways is therefore an integral part in early drug development, as any alteration of metabolic enzymes may markedly influence the toxicological profile and efficacy of novel compounds. In silico methods are widely applied in drug development to complement experimental approaches. Several different tools are available for that purpose, however, for CYP enzymes they have only been applied retrospectively so far. Within this study, pharmacophore- and shape-based models and a docking protocol were generated for the prediction of CYP1A2, 2C9, and 3A4 inhibition. All theoretically validated models, the validated docking workflow, and additional external bioactivity profiling tools were applied independently and in parallel to predict the CYP inhibition of 29 compounds from synthetic and natural origin. After subsequent experimental assessment of the in silico predictions, we analyzed and compared the prospective performance of all methods, thereby defining the suitability of the applied techniques for CYP enzymes. We observed quite substantial differences in the performances of the applied tools, suggesting that the rational selection of that virtual screening method that proved to perform best can largely improve the success rates when it comes to CYP inhibition prediction.
authors.affiliation: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria phone/fax:+43 512 507 58253/+43 512 507 58299.
authors.forename: Teresa
authors.initials: T
authors.lastname: Kaserer
authors.affiliation: Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstr. 14, 1090 Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Höferl
authors.affiliation: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria phone/fax:+43 512 507 58253/+43 512 507 58299.
authors.forename: Klara
authors.initials: K
authors.lastname: Müller
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Elmer
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Ganzera
authors.affiliation: Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstr. 14, 1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria phone/fax:+43 512 507 58253/+43 512 507 58299. Daniela.Schuster@uibk.ac.at.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry*; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000737:chemistry*; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry*; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry*; D004341:Drug Evaluation; D006801:Humans; D062105:Molecular Docking Simulation
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: 2D similarity; Docking; Metabolism; Pharmacophore modeling; Shape-based modeling