Introduction to Metabolizer

ChemAxon User Group Meeting Budapest 2007

György Pirok

The Biotransformation Library

The current version of the biotransformation library contains 183 Reactor compatible generic phase I. human xenobiotic CP450 biotransformatons.

Metabolite Generation with Competing Transformations

B FC

A

r1 r2 r3 r4 r5

r1 r2 r3 r4 r5

HG

r1 r2 r3 r4 r5

JI K

Predicting Metabolic Stability

1. All generic biotransformations are classified into speed categories (very fast, fast, medium, very slow, slow)

2. If the examples of a biotransformation have reaction speed data contains measurements, they can be used to predict the transformation speed of the current substrate by a special reaction similarity computation.

3. In case of some oxidative biotransformations a speed prediction can be calculated directly from the substrate.

Three levels of biotransformation speed/priority prediction

Metabolic stability prediction will be based on the prediction of the speed of transforming reactions.

B FC

A

r1 r2 r5

If a substrate is destroyed by at least one fast reaction, it is not stable!

Predicting Dominating Metabolites

Dominating metabolites are those that are accumulated in higher concetrations than others. They are produced by fast transformation routes and destroyed by slow ones.

Dominating metabolite prediction is more complex than metabolic stability prediction.

CB F

A

r1 r2 r5

r3 r5

HG

r5 r7 r8 r1 r3 r4

r5 r7 r3 r4

f(x) = ?

fast/stablemedium/mediumslow/unstable

Operating Modes

• In exhaustive metabolism mode all possible metabolites are enumerated until a given step count or a termination condition defined in Chemical Terms. Dominating metabolites can be color highlighted. Danger of combinatorial explosion.

• Selective metabolism mode generates only dominating metabolites. This reduces the chance of a combinatorial explosion and provides a much smaller metabolite set.

• Users can drive the Metaboliser in manual mode as well to modify the prediction or focus on the interesting pathways.

Metabolizer GUI development

Summary

• What will Metabolizer be?– Metabolizer will be a metabolic biotransformation prediction tool

based on the Reactor engine and other technologies.

• What will it be good for?– generating all possible metabolites of given substrates– discovering selected metabolic routes– predicting metabolic stability of given compounds– predicting dominating metabolites of given substrates– toxicity prediction tools based on Metabolizer can consider

metabolites and their concentrations

• How will I be able to access it?– Off the shelf (Metabolizer Application)– Integrating into applications (Java/.NET API, Oracle Cartidge)– Human CP450 phase I. xenobiotic biotranformation library

included– FREE for Academics

Acknowledgements

Nóra Máté, Zsolt MohácsiPlugin system, Chemical Terms Evaluator, Reactor

György T. Balogh, Eszter Papp, Virág Sági KissHuman CP450 Xenobiotic Biotransformation Library

István Cseh, Attila SzabóReactor Application, Chemical Terms Editor

József Szegezdi, Ferenc CsizmadiaProperty predictions, calculations

Szabolcs CsepregiSubstructure searching functions

Miklós VargyasChemical Terms Evaluator