Utilization of Human Nuclear Receptors as an Early Counter Screen for Off-Target Activity: A Case Study with a Compendium of 615 Known Drugs

Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/ physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen a/b, and thyroid hormone a/b receptors. Our study revealed that 4.7 and 12.4 % compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/ development. Key words: nuclear hormone receptor; in vitro; profiling; androgen receptor; progesterone receptor; estrogen receptor; thyroid receptor; hazard identificatio