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StarDrop enables you to guide your chemistry when resolving metabolism problems. The P450 models identify a molecule’s most reactive sites towards metabolism for three human cytochrome P450 enzymes: CYP3A4, CYP2D6 and CYP2C9 (accounting for approximately 95% of human Phase 1 metabolism).
• Identify the sites in a molecule that are vulnerable to attack by the major cytochrome P450 enzymes using patented quantum mechanical simulation P450 models
• Aid the redesign of compounds to overcome metabolic liabilities or, combined with other factors such as affinity or lipophilicity, indicate a risk of high metabolic rate or 'turnover'
The StarDrop P450 models are based on quantum mechanical simulations of the chemical reactions that lead to the formation of metabolites. The reaction mechanisms leading to N- and O-dealkylation, aliphatic hydroxylation, aromatic- and S-oxidation are modelled. These represent approximately 90% of the observed reactions metabolized by P450 enzymes.
It is assumed in running the models that the molecule may be a substrate for one of the P450 isoforms modeled.
The output of the StarDrop P450 models consists of:
• A Regioselectivity map of the molecule for each isoform: The relative proportion (%) of products formed by metabolism at each potential site, i.e. the most likely metabolites that will be formed if the molecule is a substrate for one of the isoforms modeled.
• A Metabolic Landscape for CYP3A4: An estimate of the absolute vulnerability of each potential site of metabolism, which is a measure of the efficiency of metabolism at that position. The category assigned to each site is indicated by the color of the bar, from red (‘labile’) to blue (‘stable’). The vertical bars indicate the degree of lability of each site on the molecule. The metabolic landscape can be used to guide the redesign of compounds that have a high metabolic turnover by cytochrome P450 enzymes, particularly CYP3A4.
• Composite Site Lability (CSL): A number between 0 and 1 measuring the overall reactivity of the molecule towards CYP3A4. A value close to 1 indicates that the metabolism is likely to be extremely efficient. It is important to note that CSL is not a prediction of the rate of metabolism.
Download our Fequently Asked Questions document for further information about the P450 models.
StarDrop™, Glowing Molecule™ and Auto-Modeler™ are trademarks of Galapagos NV and/or its affiliates
