Cytochrome P450 and drug metabolism
The Cytochrome P450 (CYP) enzymes constitute one of the most effective defense systems in the organism against foreign compounds (xenobiotic). We are focusing on the CYP 2C9, 2C19, 2D6 and 3A4 isoforms, since they are responsible for most of the drug metabolism.
The aim of this work is to develop and apply methods which are able to predict which compounds will bind and eventually be metabolised by the different CYPs. In case a compound is metabolized, it is also important to be able to predict what metabolite that was generated.
We make use of and develop computer-based methods for this purpose. For example, we have applied machine-learning and QSAR-based methods for classification of substrates and non-substrates, investigated the rate-limiting steps of the oxidations reactions with DFT methods, and constructed transition state force fields to study the reactions of the substrate with the entire enzyme.
SMARTCyp is a method for prediction of drug metabolism mediated by cytochrome P450 2C9, 2D6 and 3A4, as well as a general reactivity model applicable to any P450 isoform.
More information on SMARTCyp as well as
The contribution of atom accessibility to site of metabolism models for cytochromes P450. 2013. Molecular Pharmaceutics, 10 (4): 1216–1223.
Enrichment of true positives from structural alerts through the use of novel atomic fragment based descriptors. 2013. Molecular Informatics, 32 (1): 81–86.
RS-WebPredictor: A server for predicting CYP-mediated sites of metabolism on drug-like molecules. 2013. Bioinformatics, 29 (4): 497-498.
Nitrogen inversion barriers affect the N-oxidation of tertiary alkylamines by cytochromes P450. 2013. Angewandte Chemie International Edition, 52(3): 993-997.
Quantum-mechanical studies of reactions performed by cytochrome P450 enzymes. 2012. Current Inorganic Chemistry, 2(3): 292-315.
Theoretical study of the cytochrome P450 mediated metabolism of phosphorodithioate pesticides. 2012. Journal of Chemical Theory and Computation, 8(8): 2706-2712.
RS-Predictor models augmented with SMARTCyp reactivities: Robust metabolic regioselectivity predictions for nine CYP isozymes. 2012. Journal of Chemical Information and Modeling, 52(6): 1637-1659.
Predicting drug metabolism by cytochrome P450 2C9: Comparison with the 2D6 and 3A4 isoforms. 2012. ChemMedChem, 7(7): 1202-1209.
Ligand-based site of metabolism prediction for cytochrome P450 2D6. 2012. ACS Medicinal Chemistry Letters, 3(1): 69-73.
Comment on "binding free energies of inhibitors to iron porphyrin complex as a model for cytochrome p450". 2012. Biopolymers, 97(4): 250-251.
Do two different reaction mechanisms contribute to the hydroxylation of primary amines by cytochromes P450? 2011. Journal of Chemical Theory and Computation, 7(10): 3399-3404.
RS-Predictor: A new tool for predicting sites of cytochrome P450-mediated metabolism applied to CYP 3A4. 2011. Journal of Chemical Information and Modeling, 51(7): 1667-1689.
The SMARTCyp cytochrome P450 metabolism prediction server. 2010. Bioinformatics, 26(23): 2988-2989.
SMARTCyp: A 2D method for prediction of cytochrome P450-mediated drug metabolism. 2010. ACS Medicinal Chemistry Letters, 1(3): 96-100.
Fast prediction of cytochrome P450 mediated drug metabolism. 2009. ChemMedChem, 4(12): 2070-2079.
The accuracy of geometries for iron porphyrin complexes from density functional theory. 2009. The Journal of Physical Chemistry A, 113 (43): 11949-11953.
Virtual screening and prediction of site of metabolism for cytochrome P450 1A2 ligands. 2009. Journal of Chemical Information and Modeling, 49 (1): 43–52.
Classification of cytochrome P450 1A2 inhibitors and non-inhibitors by machine learning techniques. 2009. Drug Metabolism & Disposition, 37(3): 658-664.
Prediction of activation energies for aromatic oxidation by cytochrome P450. 2008. The Journal of Physical Chemistry A, 112 (50): 13058-13065.
Sulfoxide, sulfur, and nitrogen oxidation and dealkylation by cytochrome P450. 2008. Journal of Chemical Theory and Computation, 4 (8): 1369-1377.
Transition-state docking of flunitrazepam and progesterone in cytochrome P450. 2008. Journal of Chemical Theory and Computation, 4 (4): 673–681.
General transition-state force field for cytochrome P450 hydroxylation. 2007. Journal of Chemical Theory and Computation, 3 (5): 1765 -177.
Dynamics of water molecules in the active-site cavity of human cytochromes P450. 2007. The Journal of Physical Chemistry B, 111(19): 5445-5457.
Prediction of activation energies for hydrogen abstraction by cytochrome P450. 2006. Journal of Medicinal Chemistry, 49(22): 6489-6499.