Abstract
In drug design and discovery, binding affinity and selectivity are two basic properties of a drug candidate. Opioid receptors (ORs) are the main targets of strong analgesics. Like some other class A members of G-protein-coupled receptors (GPCRs), ORs exhibit complex selectivity on their ligands. The diversity of binding activity and selectivity among opioids has deeply attracted researchers for a long time. To investigate the subtype selectivity of μ, δ and κ ORs in detail, using the κ-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-μ/δ/κ-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the μ-subtype was the 2.63 position, which affected the efficacy of JDTic through changing the dynamics of the Q2.60 residue. In addition to the 2.63-position residue, the 7.35 position was the other crucial aspect of JDTic selectivity for the δ-subtype. Based on the results, we suggest a new concept, the “message-address-efficacy” hypothesis, to explain the relationships among the affinity, selectivity and function between ORs and opioids. Thus, all the detailed dynamics of JDTic-bound ORs might be helpful to deeply understand the subtype selectivity and binding mechanisms of other GPCRs.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Lagerstrom MC, Schioth HB . Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 2008; 7: 339–57.
Lee SM, Booe JM, Pioszak AA . Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs. Eur J Pharmacol 2015; 763: 196–205.
Mallipeddi S, Janero DR, Zvonok N, Makriyannis A . Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets. Biochem Pharmacol 2017; 128: 1–11.
Zhou L, Bohn LM . Functional selectivity of GPCR signaling in animals. Curr Opin Cell Biol 2014; 27: 102–8.
Kolakowski LF Jr . GCRDb: a G-protein-coupled receptor database. Receptors Channels 1994; 2: 1–7.
Katritch V, Cherezov V, Stevens RC . Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 2013; 53: 531–56.
Beaulieu JM . In vivo veritas, the next frontier for functionally selective GPCR ligands. Methods 2016; 92: 64–71.
Eberle A, Leukart O, Schiller P, Fauchere JL, Schwyzer R . Hormone--receptor interactions: [4-carboranylalanine, 5-leucine]-enkephalin as a structural probe for the opiate receptor. FEBS Lett 1977; 82: 325–8.
Chavkin C, Goldstein A . Specific receptor for the opioid peptide dynorphin: structure--activity relationships. Proc Natl Acad Sci U S A 1981; 78: 6543–7.
Schwyzer R . ACTH: a short introductory review. Ann N Y Acad Sci 1977; 297: 3–26.
Portoghese P, Sultana M, Takemori A . Design of peptidomimetic delta opioid receptor antagonists using the message-address concept. J Med Chem 1990; 33: 1714–20.
Portoghese PS, Sultana M, Takemori A . Naltrindole, a highly selective and potent non-peptide δ opioid receptor antagonist. Eur J Pharmacol 1988; 146: 185–6.
Portoghese PS . Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol Sci 1989; 10: 230–5.
Filizola M, Devi LA . Grand opening of structure-guided design for novel opioids. Trends Pharmacol Sci 2013; 34: 6–12.
Cox BM . Recent developments in the study of opioid receptors. Mol Pharmacol 2013; 83: 723–8.
Lipkowski AW, Tam SW, Portoghese PS . Peptides as receptor selectivity modulators of opiate pharmacophores. J Med Chem 1986; 29: 1222–5.
Mansour A, Taylor LP, Fine JL, Thompson RC, Hoversten MT, Mosberg HI, et al. Key residues defining the mu-opioid receptor binding pocket: a site-directed mutagenesis study. J Neurochem 1997; 68: 344–53.
Ballesteros JA, Weinstein H . Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 1995; 25: 366–428.
Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, et al. Structure of the delta-opioid receptor bound to naltrindole. Nature 2012; 485: 400–4.
Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, et al. Structure of the human kappa-opioid receptor in complex with JDTic. Nature 2012; 485: 327–32.
Bonner G, Meng F, Akil H . Selectivity of mu-opioid receptor determined by interfacial residues near third extracellular loop. Eur J Pharmacol 2000; 403: 37–44.
Filizola M, Devi LA . Structural biology: how opioid drugs bind to receptors. Nature 2012; 485: 314–7.
Sharma SK, Jones RM, Metzger TG, Ferguson DM, Portoghese PS . Transformation of a kappa-opioid receptor antagonist to a kappa-agonist by transfer of a guanidinium group from the 5′- to 6′-position of naltrindole. J Med Chem 2001; 44: 2073–9.
Jones RM, Hjorth SA, Schwartz TW, Portoghese PS . Mutational evidence for a common kappa antagonist binding pocket in the wild-type kappa and mutant mu[K303E] opioid receptors. J Med Chem 1998; 41: 4911–4.
Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS . Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus. J Med Chem 2001; 44: 857–62.
Metzger TG, Ferguson DM . On the role of extracellular loops of opioid receptors in conferring ligand selectivity. FEBS Lett 1995; 375: 1–4.
Thomas JB, Atkinson RN, Rothman RB, Fix SE, Mascarella SW, Vinson NA, et al. Identification of the first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid κ receptor antagonist activity. J Med Chem 2001; 44: 2687–90.
Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. Discovery of aminobenzyloxyarylamides as kappa opioid receptor selective antagonists: application to preclinical development of a kappa opioid receptor antagonist receptor occupancy tracer. J Med Chem 2011; 54: 8000–12.
Carroll FI . Carlezon WA Jr. Development of kappa opioid receptor antagonists. J Med Chem 2013; 56: 2178–95.
Thomas JB, Atkinson RN, Vinson NA, Catanzaro JL, Perretta CL, Fix SE, et al. Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)- 3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro- 3-isoquinolinecarboxamide as a novel potent and selective opioid kappa receptor antagonist. J Med Chem 2003; 46: 3127–37.
Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, et al. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 2012; 485: 321–6.
Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA, Cherezov V, et al. Molecular control of delta-opioid receptor signalling. Nature 2014; 506: 191–6.
Spassov VZ, Flook PK, Yan L . LOOPER: a molecular mechanics-based algorithm for protein loop prediction. Protein Eng Des Sel 2008; 21: 91–100.
Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 2010; 31: 671–90.
Vanommeslaeghe K . MacKerell AD Jr. Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing. J Chem Inf Model 2012; 52: 3144–54.
Vanommeslaeghe K, Raman EP . MacKerell AD Jr. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J Chem Inf Model 2012; 52: 3155–68.
Lomize AL, Pogozheva ID, Mosberg HI . Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model 2011; 51: 930–46.
Lomize MA, Pogozheva ID, Joo H, Mosberg HI, Lomize AL . OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res 2012; 40: D370–6.
Klauda JB, Venable RM, Freites JA, O'Connor JW, Tobias DJ, Mondragon-Ramirez C, et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B 2010; 114: 7830–43.
Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph 1996; 14: 33–8.
Hess B, Kutzner C, van der Spoel D, Lindahl E . GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 2008; 4: 435–47.
Barducci A, Bonomi M, Parrinello M . Metadynamics. Wiley Interdiscip. Rev Comp Mol Sci 2011; 1: 826–43.
Barducci A, Bussi G, Parrinello M . Well-tempered metadynamics: a smoothly converging and tunable free-energy method. Phys Rev Lett 2008; 100: 020603.
Laio A, Parrinello M . Escaping free-energy minima. Proc Natl Acad Sci U S A 2002; 99: 12562–6.
Tribello GA, Bonomi M, Branduardi D, Camilloni C, Bussi G . PLUMED 2: New feathers for an old bird. Comput Phys Commun 2014; 185: 604–13.
Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology 2014; 77: 131–44.
Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016; 537: 185–90.
Acknowledgements
All the simulations were performed using the high-performance cluster kindly provided by Prof Bang-ce YE of the State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology. This work was supported by the National Key Research and Development Program of China (Grant 2016YFA0502304), the National Natural Science Foundation of China (Grants 81673356 and U1603122) and the 111 Project (Grant B07023).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary files are available at the website of Acta Pharmacologica Sinica.
Supplementary information
Supplementary Information
Supplementray Figures and table (DOC 2321 kb)
Rights and permissions
About this article
Cite this article
Cheng, Jx., Cheng, T., Li, Wh. et al. Computational insights into the subtype selectivity and “message-address-efficacy” mechanisms of opioid receptors through JDTic binding and unbinding. Acta Pharmacol Sin 39, 482–491 (2018). https://doi.org/10.1038/aps.2017.132
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/aps.2017.132
Keywords
This article is cited by
-
Structural basis of tolvaptan binding to the vasopressin V2 receptor
Acta Pharmacologica Sinica (2024)
