Reaction site mapping of xenobiotic biotransformations

被引:79
作者
Boyer, Scott [1 ]
Arnby, Catrin Hasselgren
Carlsson, Lars
Smith, James
Stein, Viktor
Glen, Robert C.
机构
[1] AstraZeneca R&D, Safety Assessment, S-43183 Molndal, Sweden
[2] Univ Cambridge, Chem Lab, Unilever Ctr Mol Sci Informat, Cambridge CB2 1EW, England
关键词
D O I
10.1021/ci600376q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Predictive metabolism methods can be used in drug discovery projects to enhance the understanding of structure-metabolism relationships. The present study uses data mining methods to exploit biotransformation data that have been recorded in the MDL Metabolite database. Reacting center fingerprints were derived from a comparison of substrates and their corresponding products listed in the database. This process yields two fingerprint databases: all atoms in all substrates and all reacting centers. The metabolic reaction data are then mined by submitting a new molecule and searching for fingerprint matches to every atom in the new molecule in both databases. An "occurrence ratio" is derived from the fingerprint matches between the submitted compound and the reacting center and substrate fingerprint databases. Normalization of the occurrence ratio within each submitted molecule enables the results of the search to be rank-ordered as a measure of the relative frequency of a reaction occurring at a specific site within the submitted molecule. Predictive performance that would allow this method to be used by drug discovery teams to generate useful hypotheses regarding structure metabolism relationships was observed.
引用
收藏
页码:583 / 590
页数:8
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