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Unique Users-Initiated Biotransformation Reactions for Analysis of Xenobiotic Metabolism
Poster Title: Unique Users-Initiated Biotransformation Reactions for Analysis of Xenobiotic Metabolism
Submitted on 11 Jul 2018
Author(s): Richard Lee, Rytis Kubilius, Vitaly Lashin, Alexandr Sakharov, Anne Marie Smith
Affiliations: Advanced Chemistry Development, Inc. (ACD/Labs); 8 King Street East, Suite 107; Toronto, ON, Canada; M5C 1B5
This poster was presented at 66th American Society for Mass Spectrometry Conference
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Poster Information
Abstract: Introduction
Typical analysis of examining xenobiotic metabolism studies involves the use of liquid chromatography coupled to a high resolution mass spectrometer. There are a number of strategies involved for processing this type of data using native vendor software and other 3 rd party solutions. These often include the use of mass defect filtering, isotope matching, inclusion/exclusion lists and may involve a database of known established Phase 1 and Phase 2 biotransformations rules to determine the presence of these components. However, there are challenges when uncommon biotransformations are present in the biological system which are often overlooked. Here, we present a method for users to input unique/uncommon metabolic reactions via a structure design system.

Here we present a new method for custom biotransformation rules to be implemented as part of an overall xenobiotic analysis solution. This new structure design interface is incorparated in a metabolite identification solution that includes data import, chemical structure handling, data processing, and databasing the processed results. This new interface allows the user to input fragment moieties and conjugating groups to describe specific reactions used as part of the data processing routine. The data processing methodology includes metabolite prediction (both native and user created), component detection, structure elucidation, and biotransformation map creation.

Preliminary Data
In the analysis of xenobiotic metabolism studies, there have been significant hardware advancement to aid in these types of studies. In contrast, informatics systems designed to process the data has not seen the same level of innovation or utility. Most software solutions involve a combination mass defect filtering, accurate mass, isotope matching, and inclusion/exclusion lists. They may employ a small database of biotransformations describing typical Phase 1 and Phase 2 metabolic reactions, which are often numerical tables with mass differences. Moreover, in most cases these solutions do not incorporate chemical structures to any appreciable extent. However, there are metabolism solutions that are available which include data processing and/or prediction algorithms for generating expected structures. In these solutions, the potential metabolite structures which are generated are only as reliable was the prediction algorithm. Predicting typical phase 1 and phase 2 reactions are well established mainly for typical enzymatic systems such as P450. In the cases where unique or uncommon metabolites are present, these systems have a high rate of failure. Here, we describe a method to input unique metabolic reactions and map the functional group transformations. The unique biotransformations are captured within a drawing program which allows for clear representation of a chemical reaction. These reactions can then be stored as part of a single reactions DB or several DBs where the end user can select the specific DB(s) required for their analysis. During the data processing routine these reactions can complement the already pre-existing metabolite prediction engine to further increase the chemical space, in order to mitigate any overlooked metabolites.

Novel Aspect
A unique structure design interface for analysis of uncommon biotransformation reactions.
Summary: ACD/Labs has developed an interface for user-defined metabolic reactions to address the lack of well represented biotransformations. User reactions are drawn in a generic biotransformation scheme and can be seamlessly integrated with the pre-existing prediction engine, allowing for increased chemical coverage during analysis of xenobiotic metabolism studies with the MetaSense solutionReferences: R. E. Hoagland, R. M. Zablotowicz, and J. C. Hall Pesticide Biotransformation in Plants and Microorganisms. December 1, 2000 , 2-

Hatzios, K. K. J. C. Hall, R. E. Hoagland, and R. M. Zablotowicz. Pesticide Biotransformation in Plants and Microorganisms: Similarities
and Divergences. Washington, DC: American Chemical Society. 2001

Hatzios, K. K. Biotransformations of herbicides in higher plants. R. Grover and A. J. Cessna, eds. Environmental Chemistry of
Herbicides. Boca Raton, FL: CRC Press. 1991, 141–185
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