Rational Design Biased Compounds against μ‑Opioid Receptor

  • ACS Pharmacol Transl Sci. 2025 Apr 8;8(7):1996-2008. doi: 10.1021/acsptsci.5c00055.
Chenyang Wu  1  2 ,  Yi Li  3 ,  Horst Vogel  1  4  5 ,  Shuguang Yuan  1  3
Affiliations
  • 1. The Research Center for Computer-Aided Drug Discovery, The Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. AlphaMol Science Ltd, Shenzhen 518055, China.
  • 4. Shenzhen University of Advanced Technology, Shenzhen 518055, China.
  • 5. Institut des Sciences et Ingénierie Chimiques (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
PMID: 40672676 DOI: 10.1021/acsptsci.5c00055
Abstract

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.

Keywords
G protein biased signaling; G protein-coupled receptors; computational design; mu-opioid receptor; partial agonist.
Products