P450 metabolism

Quantum mechanical simulation of drug metabolism

Using StarDrop's P450 metabolism models you can quickly identify the regions of your compounds that are most vulnerable to metabolism by the major drug metabolising isoforms of cytochrome P450 and predict the metabolites formed.

Regioselectivty and WhichP450™ Models

StarDrop's P450 metabolism models predict the regioselectivity of metabolism by seven of the major drug metabolising isoforms of Cytochrome P450 enzymes. Each model identifies the sites at which metabolism is likely to occur and the corresponding metbolites if the compound is a substrate of that isoform.

StarDrop's CYP450 module enables you to predict metabolic vulnerability for the P450 isoforms:

  • CYP3A4
  • CYP2D6
  • CYP2C9
  • CYP1A2
  • CYP2C19
  • CYP2C8
  • CYP2E1

StarDrop's WhichP450 model informs you which Cytochrome P450 isoforms are most likely to be responsible for the phase I metabolism of your compounds. Combined with the models of regioselectivities of metabolism by each isoform, this model aids in the prediction of the metabolites most likely to be formed by P450-mediated metabolism. Understanding how a compound is metabolised enables identification and analysis of its potential metabolites, and guides the design of molecules with a reduced risk of drug-drug interactions or variations in exposure across the patient population.

For further information, take a look at our J. Chem. Inf. Model, ‘Predicting Regioselectivity and Lability of Cytochrome P450 Metabolism Using Quantum Mechanical Simulations' and our J. Comput.-Aided Mol. Des paper 'WhichP450 – A Multi-class Categorical Model to Predict the Major Metabolising CYP450 Isoform for a Compound', where we discuss the methods underlying the regioselectivity WhichP450 models.

Metabolic Lability

While valuable, predicting the relative proportion of metabolite formation at different sites on a molecule is only a partial solution to designing more stable molecules. Therefore, StarDrop's quantum mechanical approach goes beyond other methods that predict only the sites of metabolism, to provide a measure of the vulnerability of each site to metabolism by CYP3A4 on an absolute scale. This 'metabolic landscape' provides valuable additional information that guides the redesign of compounds to improve their metabolic stability.

The P450 models are available as an optional module for StarDrop. To find out more about StarDrop and the P450 models,or to arrange an online demonstration and perhaps try StarDrop for yourself, please contact us.

StarDrop - P450 Metabolic Regioselectivity StarDrop - P450 Metabolite prediction StarDrop - P450 Metabolism
For an example of how StarDrop's P450 models can be used in compound design take a look at the case study "Redesign to resolve metabolic liabilities"
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