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Introduction to Metabolizer ChemAxon User Group MeetingBudapest 2007 György Pirok.

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Presentation on theme: "Introduction to Metabolizer ChemAxon User Group MeetingBudapest 2007 György Pirok."— Presentation transcript:

1 Introduction to Metabolizer ChemAxon User Group MeetingBudapest 2007 György Pirok

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

3 Metabolite Generation with Competing Transformations BFC A r1r2r3r4r5 r1r2r3r4r5 HG r1r2r3r4r5 JIK

4 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. BFC A r1r2r5 If a substrate is destroyed by at least one fast reaction, it is not stable!

5 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. C B F A r1r2r5 r3r5 H G r5r5 r7r7r8r8 r1 r3r4 r5r5 r7r7 r3r4 f (x) = ? fast/stable medium/medium slow/unstable

6 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.

7 Metabolizer GUI development

8 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

9 Acknowledgements Nóra Máté, Zsolt Mohácsi Plugin system, Chemical Terms Evaluator, Reactor György T. Balogh, Eszter Papp, Virág Sági Kiss Human CP450 Xenobiotic Biotransformation Library István Cseh, Attila Szabó Reactor Application, Chemical Terms Editor József Szegezdi, Ferenc Csizmadia Property predictions, calculations Szabolcs Csepregi Substructure searching functions Miklós Vargyas Chemical Terms Evaluator

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