Development of a Predictive Multiple Reaction Monitoring (MRM) Model for High-Throughput ADME Analyses Using Learning-to-Rank (LTR) Techniques

Multiple Reaction Monitoring (MRM) is an important MS/MS technique commonly used in drug discovery and development, allowing for the selective and sensitive quantification of compounds in complex matrices. However, compound optimization can be resource intensive and requires experimental determination of product ions for each compound. In this study, we developed a Learning-to-Rank (LTR) model to predict the product ions directly from compound structures, eliminating the requirement for MRM optimization experiments. Experimentally determined MRM conditions for 5757 compounds were used to develop the model. Using the MassChemSite software, theoretical fragments and their mass-to-charge ratios were generated, which were then matched to the experimental product ions to create a data set. Each possible fragment was ranked based on its intensity in the experimental data. Different LTR models were built on a training split. Hyperparameter selection was performed using 5-fold cross validation. The models were evaluated using the Normalized Discounted Cumulative Gain at top k (NDCG@k) and the Coverage at top k (Coverage@k) metrics. Finally, the model was applied to predict MRM conditions for a prospective set of 235 compounds in high-throughput Caco-2 permeability and metabolic stability assays, and quantification results were compared to those obtained with experimentally acquired MRM conditions. The LTR model achieved a NDCG@5 of 0.732 and Coverage@5 of 0.841 on the validation split, and its predictions led to 97% of biologically equivalent results in the Caco-2 permeability and metabolic stability assays.