Simulation of chemical metabolism for fate and hazard assessment. IV. Computer-based derivation of metabolic simulators from documented metabolism maps

Computer simulation of xenobiotic metabolism and degradation is usually performed proceeding from a set of expert-developed rules modelling the actual enzyme-driven chemical reactions. With the accumulation of extensive metabolic pathway data, the analysis required to derive such chemical reaction patterns has become more objective, but also more convoluted and demanding. Herein we report on our computer-based approach for the analysis of metabolic maps, leading to the construction of reaction rules statistically suitable for simulation purposes. It is based on the set of so-called bare transformations which encompass all unique reaction patterns as obtained by a heuristically enhanced maximum common subgraph algorithm. The bare transformations guarantee that no existing metabolite is missed in simulation at the expense of an enormous amount of false positive predictions. They are rendered more selective by correlating the generated true and false positives to the locations of typical chemical functional groups in the potential reactants. The approach and its results are illustrated for a metabolic map collection of 15 cycloalkanes.