Drug metabolism is a common cause of adverse drug reactions. Drug molecules can be metabolized into reactive metabolites, which can conjugate to biomolecules, like protein and DNA, in a process termed bioactivation. To mitigate adverse reactions caused by bioactivation, both experimental and computational screening assays are utilized. Experimental assays for assessing the formation of reactive metabolites are low throughput and expensive to perform, so they are often reserved until later stages of the drug development pipeline when the drug candidate pools are already significantly narrowed. In contrast, computational methods are high throughput and cheap to perform to screen thousands to millions of compounds for potentially toxic molecules during the early stages of the drug development pipeline. Commonly used computational methods focus on detecting and structurally characterizing reactive metabolite–biomolecule adducts or predicting sites on a drug molecule that are liable to form reactive metabolites. However, such methods are often only concerned with the structure of the initial drug molecule or of the adduct formed when a biomolecule conjugates to a reactive metabolite. Thus, these methods are likely to miss intermediate metabolites that may lead to subsequent reactive metabolite formation. To address these shortcomings, we create XenoNet, a metabolic network predictor, that can take a pair of a substrate and a target product as input and (1) enumerate pathways, or sequences of intermediate metabolite structures, between the pair, and (2) compute the likelihood of those pathways and intermediate metabolites. We validate XenoNet on a large, chemically diverse data set of 17 054 metabolic networks built from a literature-derived reaction database. Each metabolic network has a defined substrate molecule that has been experimentally observed to undergo metabolism into a defined product metabolite. XenoNet can predict experimentally observed pathways and intermediate metabolites linking the input substrate and product pair with a recall of 88 and 46%, respectively. Using likelihood scoring, XenoNet also achieves a top-one pathway and intermediate metabolite accuracy of 93.6 and 51.9%, respectively. We further validate XenoNet against prior methods for metabolite prediction. XenoNet significantly outperforms all prior methods across multiple metrics. XenoNet is available at .

Drug-drug interactions account for up to 30% of adverse drug reactions. Increasing prevalence of electronic health records (EHRs) offers a unique opportunity to build machine learning algorithms to identify drug-drug interactions that drive adverse events. In this study, we investigated hospitalizations’ data to study drug interactions with non-steroidal anti-inflammatory drugs (NSAIDS) that result in drug-induced liver injury (DILI). We propose a logistic regression based machine learning algorithm that unearths several known interactions from an EHR dataset of about 400,000 hospitalization. Our proposed modeling framework is successful in detecting 87.5% of the positive controls, which are defined by drugs known to interact with diclofenac causing an increased risk of DILI, and correctly ranks aggregate risk of DILI for eight commonly prescribed NSAIDs. We found that our modeling framework is particularly successful in inferring associations of drug-drug interactions from relatively small EHR datasets. Furthermore, we have identified a novel and potentially hepatotoxic interaction that might occur during concomitant use of meloxicam and esomeprazole, which are commonly prescribed together to allay NSAID-induced gastrointestinal (GI) bleeding. Empirically, we validate our approach against prior methods for signal detection on EHR datasets, in which our proposed approach outperforms all the compared methods across most metrics, such as area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC).

Adverse drug metabolism often severely impacts patient morbidity and mortality. Unfortunately, drug metabolism experimental assays are costly, inefficient, and slow. Instead, computational modeling could rapidly flag potentially toxic molecules across thousands of candidates in the early stages of drug development. Most metabolism models focus on predicting sites of metabolism (SOMs): the specific substrate atoms targeted by metabolic enzymes. However, SOMs are merely a proxy for metabolic structures: knowledge of an SOM does not explicitly provide the actual metabolite structure. Without an explicit metabolite structure, computational systems cannot evaluate the new molecule's properties. For example, the metabolite's reactivity cannot be automatically predicted, a crucial limitation because reactive drug metabolites are a key driver of adverse drug reactions (ADRs). Additionally, further metabolic events cannot be forecast, even though the metabolic path of the majority of substrates includes two or more sequential steps. To overcome the myopia of the SOM paradigm, this study constructs a well-defined systemtermed the metabolic forestfor generating exact metabolite structures. We validate the metabolic forest with the substrate and product structures from a large, chemically diverse, literature-derived dataset of 20 736 records. The metabolic forest finds a pathway linking each substrate and product for 79.42% of these records. By performing a breadth-first search of depth two or three, we improve performance to 88.43 and 88.77%, respectively. The metabolic forest includes a specialized algorithm for producing accurate quinone structures, the most common type of reactive metabolite. To our knowledge, this quinone structure algorithm is the first of its kind, as the diverse mechanisms of quinone formation are difficult to systematically reproduce. We validate the metabolic forest on a previously published dataset of 576 quinone reactions, predicting their structures with a depth three performance of 91.84%. The metabolic forest accurately enumerates metabolite structures, enabling promising new directions such as joint metabolism and reactivity modeling.

No abstract

List of Figures4.4 Bond epoxidation scores accurately (BES) identify sites of epoxidation (SOEs). 4.5 The importance of specific descriptors to the bond epoxidation model. . . . . . 4.6 Bond epoxidation scores (BES) accurately identified both aromatic and double bond sites of epoxidation. .