Rational Design Biased Compounds against μ-Opioid Receptor

Agonists targeting the μ-opioid receptor (MOR) are the most effective analgesics, but their clinical use is limited by adverse side effects which are partly induced by β-arrestin signaling. Here, we combined in silico methods and cell-based functional assays to design novel structural scaffold molecules with high affinity that were biased at the G protein signaling of MOR. Furthermore, we explored the molecular mechanism of G protein subtype preference via computational methods. The results of our studies provide an insightful view into the ligand-MOR binding mode, which could serve as an important guide for the design of next-generation MOR ligands with reduced side effects.