Structural Assessment of Agonist Efficacy in the μ-Opioid Receptor: Morphine and Fentanyl Elicit Different Activation Patterns

Over the past two decades, opioid epidemic in United States and Canada has evidenced need for a better understanding of molecular mechanisms medications used to fight pain. Morphine fentanyl are widely opiate-mediated analgesia treatment chronic These compounds target μ-opioid receptor (MOR), class A G protein-coupled (GPCR). In light described higher efficacy with respect morphine, we have performed independent μs-length unbiased dynamics (MD) simulations MOR complexes each these ligands, including antagonist naltrexone as negative control. Consequently, MD totaling 58 μs been conducted elucidate at atomic level ligand-specific activity signal transmission MOR. particular, identified stable binding poses morphine fentanyl, which interact differently Different ligand–receptor interaction landscapes directly induce sidechain conformational changes orthosteric pocket residues: Asp1493.32, Tyr1503.33, Gln1262.60, Lys2355.39. The induced conformations determine Asp1493.32–Tyr3287.43 sidechain–sidechain interactions Trp2956.48–Ala2425.46 sidechain–backbone H-bond formations, well Met1533.36 changes. addition differences ligand binding, different intracellular observed preferentially activates transmembrane (TM) helices: TM3 TM5, while TM6 TM7. As TM7 being most crucial aspect GPCR activation, this may contribute greater over morphine. computationally functional between provide new avenues design safer but not weaker drugs because it is desirable increase safety medicines without sacrificing their efficacy.