Computational Identification of Active Drug Metabolites for Human Protein Targets

Journal article, 2026

Understanding drug metabolism helps mitigate toxicity risks and anticipate pharmacological effects beyond the parent compound. Here, we explore high-confidence in vitro human bioactivity annotations from the public domain associated with a curated data set of drug-metabolite pairs. Our findings show that 26% of all drug-metabolite-target combinations contain metabolites with retained or increased bioactivity relative to their parent drugs, showing a high proportion of active metabolites with potencies below 100 nM. Moreover, these active metabolites display similar predicted physicochemical and ADME properties to their parent drugs, indicating that their biological activity may be preserved in vivo. Two key features of the identified active metabolites are noted: (1) the metabolite is more likely to be formed via an O-demethylation or an N-demethylation at a tertiary nitrogen, and (2) these drug-metabolite pairs are frequently active against the membrane receptor target class. To support further research in this area, we make our data compilation, including pairs with identified active metabolites and recorded bioactivity data, openly available.