Introduction to Metabolizer ChemAxon User Group Meeting Budapest 2007 Introduction to Metabolizer 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 J I K

Predicting Metabolic Stability F C A r1 r2 r5 Metabolic stability prediction will be based on the prediction of the speed of transforming reactions. If a substrate is destroyed by at least one fast reaction, it is not stable! Three levels of biotransformation speed/priority prediction All generic biotransformations are classified into speed categories (very fast, fast, medium, very slow, slow) 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. In case of some oxidative biotransformations a speed prediction can be calculated directly from the substrate.

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. f(x) = ? A r1 r2 r5 B C F r5 r7 r3 r5 r3 r4 G H fast/stable medium/medium slow/unstable r5 r7 r8 r1 r3 r4

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? What will it be good for? 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 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