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Morphinan agonists binding to the μ-opioid receptor

Opioid drugs, such as morphine, are widely used for the treatment of acute, postoperative, and chronic pain. They exert their analgesic effects by acting on the µ-opioid receptor (µOR), a G-protein-coupled receptor (GPCR), which mediates pain perception. Unfortunately, multiple side effects and addiction issues largely limit the clinical usage of opioids. Identifying key opioid-µOR interactions that promote the receptor activation may greatly help to develop novel analgesics lacking some of the opioids’ undesirable properties [1]. Here, we study opioid analgesics binding to µOR by microsecond-scale molecular dynamics (MD), Replica Exchange with Solute Tempering (REST2) and free energy perturbations (FEP).
Our recent work [2] identified the anchoring role of µOR residues D147 and H297 for binding two prototypical opioid agonists, morphine (MOP) and hydromorphone (HMP) (Fig. 1). The two agonists in turn altered the receptor conformation by inducing upward movement of the transmembrane helix (TM) 6 relative to TM3, which disrupts the characteristic R165-T279 hydrogen bond between TM6 and TM3 and hints to an early event of the receptor activation (Fig. 1C). Moreover, we calculated the binding free energy difference between MOP and HMP by forward and backward alchemical FEP, which resulted in 1.2±1.1 and 0.8±0.8 kcal/mol, respectively. The results show qualitative agreement with in vitro measurements (0.4±0.3 kcal/mol) by our coauthors in Grünenthal GmbH (Aachen, Germany). The FEP calculations identified subtle differences between the agonists’ binding poses that likely account for the small difference in their binding affinities.

µ-ORFigure 1 - (A) Model of µOR-ligand complex embedded in a POPC lipid membrane bilayer in explicit aqueous solution containing 0.15 M sodium chloride. (B) Molecular structures of the opioid ligands studied. (C)Our findings indicate that the agonists induce TM6 displacement relative to TM3 via their interactions with the anchoring residues H297 and D147, which disrupts the T279-R165 hydrogen bond at the intracellular side of µOR.


[1] Law et al. Trends in biochemical sciences (2013) 38: 275-282.
[2] Cong et al. Plos One (2015) 10: e0135998.