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. 2016 Nov 22;55(46):6456-6466.
doi: 10.1021/acs.biochem.6b00948. Epub 2016 Nov 7.

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways

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How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways

Sebastian Schneider et al. Biochemistry. .
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Abstract

Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 μs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand-receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.

Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structure of TRV-130 and spatial distribution of its center of mass along the binding pathway. (a) Selection of the moieties used to define the interaction fingerprints employed in the analysis. The methoxy-thiophene, the pyridine, the spiro-fused tetrahydopyran-cyclopentane (6-oxaspiro[4.5]decan-9-yl moiety), and the amine moieties are delineated by dashed, dotted–dashed, solid, and dotted lines, respectively. (b) Clusters of the spatial distribution of the center of mass of TRV-130 along the binding pathway are represented by circles with areas proportional to their populations and grouped on the basis of their structural similarity. Specifically, the region in which the ligand is in contact with the membrane is shown as an orange surface, and the vestibule region is colored purple. Metastable states further inside the receptor are colored blue and green, and the orthosteric binding site is colored red. The arrows indicate transitions between clusters that were observed with higher probability during the binding simulations.
Figure 2
Figure 2
Representative structures of the clusters with the largest spatial distribution of the center of mass of TRV-130 at each MOR location. Specifically, panels a–d show ligand–receptor interactions of representative structures of clusters 2, 3, 5, and 10, respectively.
Figure 3
Figure 3
Ligand solvation upon binding. The mean values of the distance of the ligand from the center of mass of the receptor bundle as a function of ligand solvation are shown as green, blue, purple, and red points for clusters 2, 3, 5, and 10, respectively. Error bars indicate the 15 and 85% quantiles.
Figure 4
Figure 4
Most highly contributing residues to the allosteric coupling between the ligand binding pocket and the intracellular region. Specifically, residues involved in the allosteric coupling induced by TRV-130 are shown as purple spheres in panel a, whereas panel b shows residues involved in the allosteric coupling induced by morphine.
Figure 5
Figure 5
Interaction network connecting the side chains of residues in the TRV-130-bound MOR. Polar and nonpolar contacts are indicated by solid and dashed gray lines, respectively, with a thickness proportional to the interaction probability (>40%). Conserved hydration sites are denoted with gray circles, with the area being proportional to their occupancy. Residues defining the “transmitter” and the “receiver” sets are labeled in red and blue, respectively. The ligand is indicated by a red circle, while the other residues are colored according to their contribution to the co-information (increasing from light blue to purple). Only clusters of residues with five or more residues are displayed.
Figure 6
Figure 6
Interaction network connecting the side chains of residues in the morphine-bound MOR. See the legend of Figure 5 for details.

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