Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands

Sharma, Krishna K.; Cassell, Robert J.; Meqbil, Yazan J; Su, Hongyu; Blaine, Arryn T.; Cummins, Benjamin; Mores, Kendall L.; Johnson, David K.; Rijn, Richard M. van; Altman, Ryan A.

doi:10.1039/d1md00025j

Cited by 7 publications

(11 citation statements)

References 69 publications

(51 reference statements)

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“…Recently, Sharma et al reported the molecular docking of δOR complexed with the Leu-Enk derivative bearing the Tyr1-ψ[(Z)CF=CH]-Gly2 substitution using the crystal structure of PDB 6PT2 . 67 These two structures of the zwitterionic Leu-Enk bound to δOR were denoted as Docking1 and Docking2 in the present work, respectively, which were reoptimized at the SMD M06-2X/6-31+G(d) level of theory in water. In addition, Docking2 was reoptimized with the constraint of torsion angles ϕ 2 , ϕ 3 , ϕ 4 , and ϕ 5 fixed at the values of the corresponding structure of Leu-Enk bound to δOR at the same level of theory in water, which was denoted as Docking2-c.…”

Section: Resultsmentioning

confidence: 99%

“…However, the orientations of the side chain of the Phe4 residue and the carboxylate group of the Leu5 of the fully optimized conformer Docking2 were quite different from those of conformer Docking2 bound to δOR. 67 So, we located another conformer Docking2-c by the constrained optimization with four torsion angles ϕ 2 –ϕ 5 fixed at the values of conformer Docking2 bound to δOR. The values of Δ E w and Δ G w for conformer Docking2-c were 6.27 and 4.83 kcal mol –1 higher than those of the fully optimized conformer Docking2, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…According to the refined model of the zwitterionic Leu-Enk bound to δOR (PDB ID 5C1M), 67 there were favorable interactions of the charged groups NH 3 + (Tyr1), C=O(Leu5), and C–O – (Leu5) of Leu-Enk with the side chains of Asp128, Lys108, and Arg291 residues of δOR, respectively, as well as a favorable C Aryl ···H interaction of the Phe4 residue of Leu-Enk with Trp284 of δOR instead of the π···π interaction. Hence, these favorable interactions would induce the conformation of the zwitterionic Leu-Enk ( i.e.…”

Section: Resultsmentioning

confidence: 99%

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Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

2022

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The conformational preferences of Leu-enkephalin (Leu-Enk) were explored by the conformational search and density functional theory (DFT) calculations. By a combination of low-energy conformers of each residue, the initial structures of the neutral Leu-Enk were generated and optimized using the ECEPP3 force field in the gas phase. These structures were reoptimized at the HF/3-21G(d) and M06-2X levels of theory with 6-31G(d) and 6-31+G(d) basis functions. We finally located the 139 structures with the relative energy <10 kcal mol –1 in the gas phase, from which the structures of the corresponding zwitterionic Leu-Enk were generated and reoptimized at the M06-2X/6-31+G(d) level of theory using the implicit solvation model based on density (SMD) in water. The conformational preferences of Leu-Enk were analyzed using Gibbs free energies corrected by single-point energies calculated at the double-hybrid DSD-PBEP86-D3BJ/def2-TZVP level of theory in the gas phase and in water. The neutral Leu-Enk dominantly adopted a folded structure in the gas phase stabilized by three H-bonds with a βII′-bend-like motif at the Gly3–Phe4 sequence and a close contact between the side chains of Phe4 and Leu5. The zwitterionic Leu-Enk exhibited a folded structure in water stabilized by three H-bonds with double β-bends such as a βII′ bend at the Gly2–Gly3 sequence and a βI bend at the Gly3–Phe4 sequence. The calculated ensemble-averaged distance between C Gly2 α and C Leu5 α of the zwitterionic Leu-Enk in water is consistent with the value estimated from the simulated annealing using the distance constraints derived from nuclear Overhauser effect spectroscopy (NOESY) spectra in water. Interestingly, the preferred conformations of the neutral and zwitterionic Leu-Enk are new folded structures not predicted by earlier computational studies. According to the refined model of the zwitterionic Leu-Enk bound to δ-opioid receptor (δOR), there were favorable interactions of the terminal charged groups of Leu-Enk with the side chains of charged residues of δOR as well as a favorable C Aryl ···H interaction of the Phe4 residue of Leu-Enk with Trp284 of δOR. Hence, these favorable interactions would induce the folded structure of the zwitterionic Leu-Enk with double β-bends isolated in water into the “bioactive conformation” like an extended structure when binding to δOR.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

2022

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“…There was no explanation of how physicochemical properties modulated side effects. A recent study showed C -terminal amidated ENK reduced β-arrestin recruitment efficacies at MOR and KOR [ 247 ]. The role of the C -terminus is still not clear, due to the inconsistent results [ 60 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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“…This insight has spurt efforts to develop G-protein-biased δOR agonists to reduce adverse effects including seizures, paralleling similar efforts for increasing the therapeutic window through G-protein-biased agonism at other GPCRs, including the µOR. These endeavors have generated a multitude of peptides with reduced β-arrestin recruitment potency/efficacy [ 3 , 32 , 33 , 34 , 35 ]. Similarly, small molecule biased agonists have also been developed including TAN-67, KNT-127, TRV250, and most recently PN6047.…”

Section: Introductionmentioning

confidence: 99%

Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

Meqbil

Rijn

2022

Pharmaceuticals

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The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic. Yet, the therapeutic promise of the delta opioid receptor remains and thus there is a need to identify novel delta opioid receptor ligands to be optimized and selected for clinical trials. Here, we highlight recent developments involving the delta opioid receptor, the closely related mu and kappa opioid receptors, and in the broader area of the GPCR drug discovery research. We focus on the validity and utility of the available delta opioid receptor structures. We also discuss the increased ability to perform ultra-large-scale docking studies on GPCRs, the rise in high-resolution cryo-EM structures, and the increased prevalence of machine learning and artificial intelligence in drug discovery. Overall, we pose that there are multiple opportunities to enable in silico drug discovery at the delta opioid receptor to identify novel delta opioid modulators potentially with unique pharmacological properties, such as biased signaling.

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Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands

Abstract: µ Opioid receptors agonists provide potent and effective acute analgesia; however, their therapeutic window narrows considerably upon repeated administration, such as required for treating chronic pain. In contrast, bifunctional µ/δ...

Cited by 7 publications

References 69 publications

Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

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