What is Metabolizer?

Metabolizer is an application of ChemAxon for the enumeration of the metabolites of drugs and other xenobiotics and for the prediction of their likelihood.

What is metabolite prediction good for?

Metabolite prediction provides ideas about the metabolic fate of molecules. Biodegradation deactivates drugs, activates pro-drugs, and metabolites may have biological effects meaning risk for living organs. Knowing metabolic fate can help in understanding how to improve metabolic stability or how to decrease toxicity risks.

Who is interested in metabolites?

The metabolic fate of a compound can be interesting for life science researchers, such as medicinal chemists, biochemists, biologists, toxicologists, environmental scientists, bio- and cheminformaticians.

How can I install Metabolizer?

Metabolizer is part of ChemAxon's JChem package. The JChem installer installs Metabolizer on your computer.

What kind of interfaces do you provide for Metabolizer?

Metabolizer is released in the form of a desktop application with graphical user interface (GUI), command line tool for batch operations (metabolize), and app;ication programming interface (API) for developers integrating metabolite enumeration/prediction frunctionalities in their own applications.

How does Metabolizer work?

Metabolizer transforms the given substrate according to generic transformations of the current biotransformation library.

Where is the knowledge base of Metabolizer stored?

The knowledge base can be defined in a biotransformation library. A library consists of a set of generic reactions, additional rules to make transformations selective, relevant examples, literature references, ranking, and some other data.

Do you provide such a biotransformation library?

A human xenobiotic phase one biotransformation library is built-in the application for immediate use.

I cannot view/edit the content of the built-in library, why?

The built-in human biotransformation library is not editable by default, only the list of the biotransformation names and one example scheme for each are visible. If you would like to access this knowledge base with full details and/or to modify it, please contact ChemAxon to get the library in an unencrypted format.

I am interested in bacterial (plant, rat, mouse, etc.) metabolism. Do you support that?

Biotransformation libraries can be "plugged in" easily, but we currently provide a human one only. However, you can create your own bacterial biotransformation library with the Reaction Editor tool, and if you load it in Metabolizer, you will be able to predict bacterial metabolites.

Can Metabolizer enumerate multiple generations?

Yes, it is possible to enumerate multiple generations of metabolites in a batch process. The automatic enumeration is terminated at the generation specified by the generation limit.

What is reaction rank?

Each generic biotransformation is prioritised by a rank number which determines the prediction. Ranks are converted to relative reaction rates during the enumeration, but the rates are influenced by other factors as well. In general, higher ranks mean higher transformation rates.

What is formation rate?

Formation rate is a relative reaction rate calculated from the rank and it is often influenced by other calculations such as those in the selectivity rule. A metabolite with higher formation rate is produced faster than one with lower formation rate. It's value has no absolute meaning, though, just used for calculation of likelihood indicators.

What is degradation rate?

It is a similar value to the formation rate measuring the speed of degradation of a certain compound. Just like the formation rate, it is a relative parameter used internally for the calculation of likelihood indicators.

What is production?

The reactions of the biotransformation library compete with each other to transform the substrate. The estimated production value indicates the relative amount of the substrate transformed to the given metabolite in the current route. For example, a production value of 0.6 means that approximately 60% of the initial substrate is converted to the current metabolite (and even further).

What is global production?

The global production is calculated considering all alternative metabolic routes to the given metabolite.

What is accumulation?

When a metabolite is formed rapidly and degraded slowly, it accumulates. The accumulation indicator shows how quickly a metabolite is accumulated in a certain metabolic route.

What is global accumulation?

The global accumulation is calculated considering all alternative metabolic routes to the given metabolite. The metabolites with the highest global accumulations are considered major metabolites.

What do the likelihood categories stand for?

The likelihood categories distinguish metabolites by their predicted global accummulation values. Those with the highest global accummulation values are likely to be detected experimentally, while metabolites which do not accummulate (formed slowly, degraded quickly) are unlikely to reach a significant concentration. Metabolites somehow accummulating are called probable ones. You can modify the default accumulation ranges of the likelihood categories on the Range Options dialog of the Settings menu. Please note, that these estimated likelihood indicators are available only if the biotransformation library contains ranked reactions.

Can Metabolizer predict the major metabolites?

Yes, metabolites with the highest global accumulation values can be considered major metabolites.

What is the meaning of the border color?

The border colors indicate likelihood of metabolites based on your accummulation range settings. Lighter border color means less likely metabolite. You can modify the default color ranges in the Range Options dialog of the Settings menu.

How are the metabolites sorted in the Metabolizer application?

On the Tree page, child metabolites are sorted in their formation order, the first child is has the highest formation rate. The Flow page displays metabolites in global accummulation order. The first metabolites are the major ones.

Can I control how many metabolites are generated?

You can modify the default limit for the maximum number of generations to influence the size of the metabolic tree in automatic enumeration modes.

What is a termination condition?

A termination condition is a Chemical Terms expression evaluated for each metabolite runtime. It can be defined to prevent the further metabolism of certain compounds.

What is an exclude condition?

An exclude condition is another Chemical Terms expression to blacklist compounds. Excluded metabolites do not appear in the output.

I would like to examine several generations, how can I avoid combinatorial explosion?

The "exhaustive" enumeration method may calculate a large number of metabolites in several generations which can be time and memory intensive. The fast enumeration mode, however, allows quick enumeration of the most important metabolic routes. It does not enumerate slowly formed metabolites further saving significant computation time but still resulting the same major metabolites as the exhaustive execution.

Can I discover major pathways manually in the Metabolizer application?

Child metabolites in the Tree view are sorted by their predicted formation rates. So you have a good chance to discover major metabolic routes always opening the first one or two child metabolites.

Can I load a previously saved results?

Yes, you can re-load previously saved metabolism as long as the same biotransformation library is available. You cannot load exported results.

Can I export the metabolites to an SDfile?

You can export the metabolites to a wide range of chemical file formats, for example MRV, SDfile, SMILES, InChI.

Can I export the results as a list of reactions?

You can export the transforms to reaction files such as MRV, RDfile, and SMILES.

Likelihood calculation does not seem to work at all, what is wrong?

When the production/accumulation values are zero for all metabolites, your library probably does not contain ranks.