Alignment-Based Prediction of Sites of Metabolism

Journal of Chemical Information and Modeling
Christina de Bruyn KopsJohannes Kirchmair

Abstract

Prediction of metabolically labile atom positions in a molecule (sites of metabolism) is a key component of the simulation of xenobiotic metabolism as a whole, providing crucial information for the development of safe and effective drugs. In 2008, an exploratory study was published in which sites of metabolism were derived based on molecular shape- and chemical feature-based alignment to a molecule whose site of metabolism (SoM) had been determined by experiments. We present a detailed analysis of the breadth of applicability of alignment-based SoM prediction, including transfer of the approach from a structure- to ligand-based method and extension of the applicability of the models from cytochrome P450 2C9 to all cytochrome P450 isozymes involved in drug metabolism. We evaluate the effect of molecular similarity of the query and reference molecules on the ability of this approach to accurately predict SoMs. In addition, we combine the alignment-based method with a leading chemical reactivity model to take reactivity into account. The combined model yielded superior performance in comparison to the alignment-based approach and the reactivity models with an average area under the receiver operating characteristic curve of 0.85 i...Continue Reading

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Citations

Nov 25, 2018·Chemical Biology & Drug Design·Jonathan D Tyzack, Johannes Kirchmair
Mar 25, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Pramod C NairJohn O Miners
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Malte HolmerJohannes Kirchmair
Aug 8, 2017·Journal of Chemical Information and Modeling·Martin ŠíchoJohannes Kirchmair
Jul 31, 2019·Journal of Chemical Information and Modeling·Martin ŠíchoJohannes Kirchmair

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