scholarly journals Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

2020 ◽  
Vol 21 (13) ◽  
pp. 4699 ◽  
Author(s):  
Zhennan Zhao ◽  
Tingting Huang ◽  
Jiazhong Li
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Opioid Analgesics ◽  
Dynamics Simulation ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

scholarly journals Exploring the activation pathway and Gi-coupling specificity of the μ-opioid receptor

2020 ◽  
Vol 117 (42) ◽  
pp. 26218-26225
Author(s):  
Dibyendu Mondal ◽  
Vesselin Kolev ◽  
Arieh Warshel
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Thermodynamic Cycle ◽  
Activation Mechanism ◽  
Coarse Grained ◽  
Protein G ◽  
Opioid Overdose ◽  
Activation Process ◽  
Μ Opioid Receptor

Understanding the activation mechanism of the μ-opioid receptor (μ-OR) and its selective coupling to the inhibitory G protein (Gi) is vital for pharmaceutical research aimed at finding treatments for the opioid overdose crisis. Many attempts have been made to understand the mechanism of the μ-OR activation, following the elucidation of new crystal structures such as the antagonist- and agonist-bound μ-OR. However, the focus has not been placed on the underlying energetics and specificity of the activation process. An energy-based picture would not only help to explain this coupling but also help to explore why other possible options are not common. For example, one would like to understand why μ-OR is more selective to Githan a stimulatory G protein (Gs). Our study used homology modeling and a coarse-grained model to generate all of the possible “end states” of the thermodynamic cycle of the activation of μ-OR. The end points were further used to generate reasonable intermediate structures of the receptor and the Gito calculate two-dimensional free energy landscapes. The results of the landscape calculations helped to propose a plausible sequence of conformational changes in the μ-OR and Gisystem and for exploring the path that leads to its activation. Furthermore, in silico alanine scanning calculations of the last 21 residues of the C terminals of Giand Gswere performed to shed light on the selective binding of Gito μ-OR. Overall, the present work appears to demonstrate the potential of multiscale modeling in exploring the action of G protein-coupled receptors.

To probe interaction of morphine and IBNtxA with 7TM and 6TM variants of the human μ-opioid receptor using all-atom molecular dynamics simulations with an explicit membrane

2018 ◽  
Vol 20 (3) ◽  
pp. 1724-1741 ◽  
Author(s):  
Safaa Sader ◽  
Kumar Anant ◽  
Chun Wu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Opioid Receptor ◽  
Safety Profile ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

IBNtxA, a morphine derivative, is 10-fold more potent and has a better safety profile than morphine.

scholarly journals In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6079
Author(s):  
Yusuke Karasawa ◽  
Kanako Miyano ◽  
Hideaki Fujii ◽  
Takaaki Mizuguchi ◽  
Yui Kuroda ◽  
...  
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Peptides ◽  
Opioid Analgesics ◽  
Receptor Agonists ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.

scholarly journals The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqian Zhang ◽  
Hua Yu ◽  
Xiangdong Liu ◽  
Chen Song
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Calcium Release ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Hydrophobic Region ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

scholarly journals The impact of mutation L138F/L210F on the Orai channel: a molecular dynamics simulation study

2021 ◽  
Author(s):  
Xiaoqian Zhang ◽  
Hua Yu ◽  
Xiangdong Liu ◽  
Chen Song
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Calcium Release ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Hydrophobic Region ◽  
Crac Channel ◽  
Dynamics Simulations ◽  
The Impact ◽  
Basic Region

The calcium release-activated calcium (CRAC) channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the WT. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously undescribed feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

scholarly journals A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor

2019 ◽  
Vol 116 (44) ◽  
pp. 22353-22358 ◽  
Author(s):  
Zoltan Dekan ◽  
Setareh Sianati ◽  
Arsalan Yousuf ◽  
Katy J. Sutcliffe ◽  
Alexander Gillis ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Receptor Internalization ◽  
Opioid Agonists ◽  
Receptor Interactions ◽  
Biased Signaling ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations ◽  
Orally Active

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

scholarly journals Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 740 ◽  
Author(s):  
Piotr Lipiński ◽  
Piotr Kosson ◽  
Joanna Matalińska ◽  
Piotr Roszkowski ◽  
Zbigniew Czarnocki ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Opioid Receptor ◽  
Medium Size ◽  
Scoring Functions ◽  
Binding Modes ◽  
Ionic Interaction ◽  
Competitive Binding Assay ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

COMPUTATIONAL STUDY OF THE DYNAMICS OF PEPTIDE DEFORMYLASE COMPLEX FROM LEPTOSPIRA INTERROGANS: EXPLORING THE CONFORMATIONAL CHANGES OF THE SUBSTRATE POCKET

2008 ◽  
Vol 07 (05) ◽  
pp. 911-922
Author(s):  
QIANG WANG ◽  
JIANWU WANG ◽  
ZHENGTING CAI ◽  
WEIREN XU
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Peptide Deformylase ◽  
Leptospira Interrogans ◽  
Hydrophobic Cluster ◽  
Open Conformation ◽  
Ligand Free ◽  
Dynamics Simulations

The peptide deformylase from Leptospira interrogans (LiPDF) shows many unusual characteristics. The substrate pocket of formate-bound complex adopts an open conformation. However, in the actinonin-bound LiPDF complex, a slightly open substrate pocket is observed. The opening is not large enough for the inhibitor, because the CD-loop restricts the access to the active site. To explore the conformational changes of the substrate pocket, we perform a 16,000 ps molecular dynamics simulation separately on the ligand-free LiPDF and actinonin-bound LiPDF. During the molecular dynamics simulations, extensive conformational changes have taken place. The comparison of the two MD results shows that the CD-loop, hydrophilic inhibitor, and hydrophobic cluster are necessary for the reopening of the substrate pocket. In addition, Tyr71 plays an important role in mediating the movements of CD-loop, and the transition of the substrate pocket from open to semi-open only occurs in the presence of an inhibitor, which are consistent with the experiment very well.

Molecular insights into the μ-opioid receptor selective signaling

2021 ◽  
Author(s):  
Remy Sounier ◽  
Sebastien Granier ◽  
Damien Maurel ◽  
Xiaojing Cong ◽  
Helene DEMENE ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Binding Pocket ◽  
Enhanced Sampling ◽  
Intracellular Loop ◽  
Dynamic Simulations ◽  
Opioid Ligands ◽  
Μ Opioid Receptor ◽  
Selective Agonists

GPCR functional selectivity whereby a ligand discriminates specific signaling pathways has opened new opportunities for the design of safer drugs. Ligands orchestrate GPCR signaling cascades by modulating the receptor conformational landscape. Our study provides insights into the dynamic mechanism enabling opioid ligands to selectively activate the G protein over the β-arrestin pathways through the μ-opioid receptor (μOR). We combined functional assays in living cells, solution NMR spectroscopy and enhanced-sampling molecular dynamic simulations to identify the specific μOR conformations induced by G protein-selective agonists. In particular, we describe the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains, through conserved motifs in class A GPCRs. Most strikingly, the selective agonists triggered μOR conformational changes in the intracellular loop 1 and helix 8 domains, which may impair β-arrestin binding or signaling. The findings may apply to other GPCR families and provide key molecular information that could facilitate the design of selective ligands.

Sign in / Sign up

Export Citation Format

Share Document