IsoCount: Software-Assisted Localization of Biotransformations by High-Resolution Mass Spectrometry

摘要

IsoCount provides a real-world solution to assist MS analysts involved in the structural elucidation of drug metabolites by providing computer-supported assignments. The current implementation shows a high rate of success for single BTs (e.g. mono oxidation, demethylation). IsoCount will experience limitations when key product ions arise from rearrangements, not simple cleavages. IsoCount faces the same challenges as humans when multiple plausible rationalizations exist for a given ion, but has the advantage of making the analyst aware of them. By default, IsoCount will always propose a solution, even when a human would not draw a firm conclusion (i.e., when the data are ambiguous). For relatively straightforward cases, the level of formal discrimination between possible metabolism sites based on a weight of evidence approach will generally not be as discerning as that provided by an experienced analyst combining information from key ions. At the same time, IsoCount facilitates the consideration of all data by the analyst, rather than just drawing a conclusion from one or two significant product ions. Points to explore / optimise further: (1) multiple BTs. (2) relative weighting factors for the different ion types. (3) normalise the weights of ions to their spectral intensity. (4) fragmentation occurring on the BT itself (ex: bulky substituents such as glucuronide, glutathione).