Stereoselective recognition of morphine enantiomers by μ-opioid receptor

Wang, Yibo; Ngo, Van A.; Wang, Xiaohui

doi:10.1093/nsr/nwae029

Title: Stereoselective recognition of morphine enantiomers by μ-opioid receptor

Journal Article · Mon Jan 22 00:00:00 UTC 2024 · National Science Review

DOI: https://doi.org/10.1093/nsr/nwae029 · OSTI ID:2320350

^[1]; Ngo, Van A. ^[2];

^[3]

Chinese Academy of Sciences (CAS), Changchun (China)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Chinese Academy of Sciences (CAS), Changchun (China); Univ. of Science and Technology of China, Hefei (China); Beijing National Laboratory for Molecular Sciences (China)

Stereospecific recognition of chiral molecules plays a crucial role in biological systems. The μ-opioid receptor (MOR) exhibits binding affinity towards (-)-morphine, a well-established gold standard in pain management, while it shows minimal binding affinity for the (+)-morphine enantiomer, resulting in a lack of analgesic activity. Understanding how MOR stereoselectively recognizes morphine enantiomers has remained a puzzle in neuroscience and pharmacology for over half-a-century due to the lack of direct observation techniques. To unravel this mystery, we constructed the binding and unbinding processes of morphine enantiomers with MOR via molecular dynamics simulations to investigate the thermodynamics and kinetics governing MOR's stereoselective recognition of morphine enantiomers. Our findings reveal that the binding of (-)-morphine stabilizes MOR in its activated state, exhibiting a deep energy well and a prolonged residence time. In contrast, (+)-morphine fails to sustain the activation state of MOR. Furthermore, the results suggest that specific residues, namely D114^2.50 and D147^3.32, are deprotonated in the active state of MOR bound to (-)-morphine. This work highlights that the selectivity in molecular recognition goes beyond binding affinities, extending into the realm of residence time.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Natural Science Foundation of China (NSFC); USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2320350

Journal Information:: National Science Review, Journal Name: National Science Review Journal Issue: 3 Vol. 11; ISSN 2095-5138

Publisher:: China Science PublishingCopyright Statement

Country of Publication:: United States

Language:: English

References (32)

How Important is Parity Violation for Molecular and Biomolecular Chirality? Quack, Martin Angewandte Chemie International Edition, Vol. 41, Issue 24 https://doi.org/10.1002/anie.200290005	journal	December 2002
A Simple Protocol To Estimate Differences in Protein Binding Affinity for Enantiomers without Prior Resolution of Racemates Fokkens, Jasmine; Klebe, Gerhard Angewandte Chemie International Edition, Vol. 45, Issue 6 https://doi.org/10.1002/anie.200502302	journal	January 2006
Trends in the development of chiral drugs Caner, Hava; Groner, Efrat; Levy, Liron Drug Discovery Today, Vol. 9, Issue 3 https://doi.org/10.1016/S1359-6446(03)02904-0	journal	February 2004
Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation Hu, Xiaohu; Provasi, Davide; Ramsey, Steven Biophysical Journal, Vol. 118, Issue 4 https://doi.org/10.1016/j.bpj.2019.10.007	journal	February 2020
Crystal Structure of an LSD-Bound Human Serotonin Receptor Wacker, Daniel; Wang, Sheng; McCorvy, John D. Cell, Vol. 168, Issue 3 https://doi.org/10.1016/j.cell.2016.12.033	journal	January 2017
How Ligands Illuminate GPCR Molecular Pharmacology Wacker, Daniel; Stevens, Raymond C.; Roth, Bryan L. Cell, Vol. 170, Issue 3 https://doi.org/10.1016/j.cell.2017.07.009	journal	July 2017
Molecular recognition of morphine and fentanyl by the human μ-opioid receptor Zhuang, Youwen; Wang, Yue; He, Bingqing Cell, Vol. 185, Issue 23 https://doi.org/10.1016/j.cell.2022.09.041	journal	November 2022
Illuminating GPCR Signaling by Cryo-EM Safdari, Haaris Ahsan; Pandey, Shubhi; Shukla, Arun K. Trends in Cell Biology, Vol. 28, Issue 8 https://doi.org/10.1016/j.tcb.2018.06.002	journal	August 2018
How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways Schneider, Sebastian; Provasi, Davide; Filizola, Marta Biochemistry, Vol. 55, Issue 46 https://doi.org/10.1021/acs.biochem.6b00948	journal	November 2016
Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation Decherchi, Sergio; Cavalli, Andrea Chemical Reviews, Vol. 120, Issue 23 https://doi.org/10.1021/acs.chemrev.0c00534	journal	October 2020
GPCR Dynamics: Structures in Motion Latorraca, Naomi R.; Venkatakrishnan, A. J.; Dror, Ron O. Chemical Reviews, Vol. 117, Issue 1 https://doi.org/10.1021/acs.chemrev.6b00177	journal	June 2016
Delineating the Ligand–Receptor Interactions That Lead to Biased Signaling at the μ-Opioid Receptor Kelly, Brendan; Hollingsworth, Scott A.; Blakemore, David C. Journal of Chemical Information and Modeling, Vol. 61, Issue 7 https://doi.org/10.1021/acs.jcim.1c00585	journal	July 2021
Insights into the Role of Asp79 ^2.50 in β ₂ Adrenergic Receptor Activation from Molecular Dynamics Simulations Ranganathan, Anirudh; Dror, Ron O.; Carlsson, Jens Biochemistry, Vol. 53, Issue 46 https://doi.org/10.1021/bi5008723	journal	November 2014
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K _a Predictions Olsson, Mats H. M.; Søndergaard, Chresten R.; Rostkowski, Michal Journal of Chemical Theory and Computation, Vol. 7, Issue 2 https://doi.org/10.1021/ct100578z	journal	December 2010
Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene Matthes, Hans W. D.; Maldonado, Rafael; Simonin, Frédéric Nature, Vol. 383, Issue 6603 https://doi.org/10.1038/383819a0	journal	October 1996
Propagation of conformational changes during μ-opioid receptor activation Sounier, Rémy; Mas, Camille; Steyaert, Jan Nature, Vol. 524, Issue 7565 https://doi.org/10.1038/nature14680	journal	August 2015
Structural insights into µ-opioid receptor activation Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A. J. Nature, Vol. 524, Issue 7565 https://doi.org/10.1038/nature14886	journal	August 2015
Structure-based discovery of opioid analgesics with reduced side effects Manglik, Aashish; Lin, Henry; Aryal, Dipendra K. Nature, Vol. 537, Issue 7619 https://doi.org/10.1038/nature19112	journal	August 2016
The drug–target residence time model: a 10-year retrospective Copeland, Robert A. Nature Reviews Drug Discovery, Vol. 15, Issue 2 https://doi.org/10.1038/nrd.2015.18	journal	December 2015
Trends in GPCR drug discovery: new agents, targets and indications Hauser, Alexander S.; Attwood, Misty M.; Rask-Andersen, Mathias Nature Reviews Drug Discovery, Vol. 16, Issue 12 https://doi.org/10.1038/nrd.2017.178	journal	October 2017
Drug–target residence time and its implications for lead optimization Copeland, Robert A.; Pompliano, David L.; Meek, Thomas D. Nature Reviews Drug Discovery, Vol. 5, Issue 9 https://doi.org/10.1038/nrd2082	journal	August 2006
Trends in the exploitation of novel drug targets Rask-Andersen, Mathias; Almén, Markus Sällman; Schiöth, Helgi B. Nature Reviews Drug Discovery, Vol. 10, Issue 8 https://doi.org/10.1038/nrd3478	journal	August 2011
Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations Ye, Libin; Neale, Chris; Sljoka, Adnan Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03314-9	journal	April 2018
The vital role of constitutive GPCR activity in the mesolimbic dopamine system Meye, F. J.; Ramakers, G. M. J.; Adan, R. A. H. Translational Psychiatry, Vol. 4, Issue 2 https://doi.org/10.1038/tp.2013.130	journal	February 2014
An efficient strategy to estimate thermodynamics and kinetics of G protein-coupled receptor activation using metadynamics and maximum caliber Meral, Derya; Provasi, Davide; Filizola, Marta The Journal of Chemical Physics, Vol. 149, Issue 22 https://doi.org/10.1063/1.5060960	journal	December 2018
Activation mechanism of the μ-opioid receptor by an allosteric modulator Kaneko, Shun; Imai, Shunsuke; Asao, Nobuaki Proceedings of the National Academy of Sciences, Vol. 119, Issue 16 https://doi.org/10.1073/pnas.2121918119	journal	April 2022
A brief history of opiates, opioid peptides, and opioid receptors. Brownstein, M. J. Proceedings of the National Academy of Sciences, Vol. 90, Issue 12 https://doi.org/10.1073/pnas.90.12.5391	journal	June 1993
The Effect of pH on β2 Adrenoceptor Function Ghanouni, Pejman; Schambye, Hans; Seifert, Roland Journal of Biological Chemistry, Vol. 275, Issue 5 https://doi.org/10.1074/jbc.275.5.3121	journal	February 2000
Atomic-Level Characterization of the Methadone-Stabilized Active Conformation of µ-Opioid Receptor Kapoor, Abhijeet; Provasi, Davide; Filizola, Marta Molecular Pharmacology, Vol. 98, Issue 4 https://doi.org/10.1124/mol.119.119339	journal	July 2020
Stereospecific and Nonstereospecific Effects of (+)- and (—)-Morphine: Evidence for a New Class of Receptors? Jacquet, Yasuko F.; Klee, Werner A.; Rice, Kenner C. Science, Vol. 198, Issue 4319 https://doi.org/10.1126/science.199942	journal	November 1977
Kinetic and thermodynamic insights into sodium ion translocation through the μ-opioid receptor from molecular dynamics and machine learning analysis Hu, Xiaohu; Wang, Yibo; Hunkele, Amanda PLOS Computational Biology, Vol. 15, Issue 1 https://doi.org/10.1371/journal.pcbi.1006689	journal	January 2019
Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders Ribeiro, João Marcelo Lamim; Filizola, Marta Frontiers in Molecular Neuroscience, Vol. 12 https://doi.org/10.3389/fnmol.2019.00207	journal	August 2019

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
morphine enantiomers
residence time
stereoselective recognition
thermodynamics and kinetics
μ-opioid receptor

Title: Stereoselective recognition of morphine enantiomers by μ-opioid receptor

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