Recent Molecular Insights into Agonist-specific Binding to the Mu-Opioid Receptor

Opioid agonists produce their analgesic effects primarily by acting at the µ-opioid receptor (µOR). µOR agonists with different efficacies exert diverse molecular changes in the µOR which dictate the faith of the receptor’s signaling pathway and possibly it’s the degree of desensitization. Since the development of the active conformations of the µOR, growing data have been published in relation to ligand-specific changes in µOR activation. In this regard, this review summarizes recent data regarding the most studied opioid agonists in in silico µOR activation, including how these ligands are recognized by the µOR, how their binding signal is transmitted toward the intracellular parts of the µOR, and finally, what type of large-scale movements do these changes trigger in the µOR’s domains

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

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

Molecular mechanisms of fentanyl mediated β-arrestin biased signaling.

The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, binds the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates μOR β-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles