Cytochrome P450 and drug metabolism
The Cytochrome P450 (CYP) enzymes constitute one of the most effective defense systems in the organism against foreign compounds (xeneobiotics). 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 download of the java program is available on the SMARTCyp page.