In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance
- 23 June 2015
- journal article
- research article
- Published by Wiley in Molecular Informatics
- Vol. 34 (6-7), 431-457
- https://doi.org/10.1002/minf.201400192
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.Keywords
Funding Information
- Verein zur Förderung der wissenschaftlichen Ausbildung und Tätigkeit von Südtirolern an der Landesuniversität Innsbruck
- University of Innsbruck
- Young Talents Grant and a position within the Erika Cremer Habilitation Program
- Austrian Science Fund (P26782, S10711)
- InteLigand
- OpenEye
This publication has 85 references indexed in Scilit:
- CSAR Benchmark Exercise 2011–2012: Evaluation of Results from Docking and Relative Ranking of Blinded Congeneric SeriesJournal of Chemical Information and Modeling, 2013
- Interaction of human cytochrome P4503A4 with ritonavir analogsArchives of Biochemistry and Biophysics, 2012
- 7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2Chemical Research in Toxicology, 2012
- Computational Prediction of Metabolism: Sites, Products, SAR, P450 Enzyme Dynamics, and MechanismsJournal of Chemical Information and Modeling, 2012
- Leoligin, the major lignan from Edelweiss, activates cholesteryl ester transfer proteinAtherosclerosis, 2011
- Structure−Function Relationships of Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 Flavonoid DerivativesChemical Research in Toxicology, 2010
- Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural DatabaseJournal of Chemical Information and Modeling, 2010
- In Silico Studies of Polyaromatic Hydrocarbon Inhibitors of Cytochrome P450 Enzymes 1A1, 1A2, 2A6, and 2B1Chemical Research in Toxicology, 2010
- Cytochrome P450 2C9 Type II Binding Studies on Quinoline-4-Carboxamide AnaloguesJournal of Medicinal Chemistry, 2008
- Use of Simple Docking Methods To Screen a Virtual Library for Heteroactivators of Cytochrome P450 2C9Journal of Medicinal Chemistry, 2007