Advertisement

The Protein Journal

, Volume 33, Issue 3, pp 231–242 | Cite as

In Silico Study of the Structurally Similar ORL1 Receptor Agonist and Antagonist Pairs Reveal Possible Mechanism of Receptor Activation

  • Milan Senćanski
  • Ljiljana Došen-Mićović
Article

Abstract

An opioid receptor like (ORL1) receptor is a member of a family of G-protein coupled receptors. It is a new pharmaceutical target with broad therapeutic potential in the regulation of important biological functions such as nociception, mood disorders, drug abuse, learning or cardiovascular control. The crystal structure of this receptor in complex with an antagonist was determined recently (PDB ID: 4EA3). By removing the ligand and subjecting the empty receptor to molecular dynamics simulation in a solvated lipid membrane we obtained an optimized ORL1 receptor structure which could be used in a subsequent docking study of two structurally similar agonist–antagonist ligand pairs. Ligands were docked to the empty ORL1 receptor (with and without the third intracellular loop, IC3) in different orientations, and the resulting complexes were monitored during molecular dynamics simulation in order to see how the subtle differences in structure of agonists and antagonists might affect ligand–receptor interactions and trigger receptor activation. It was established that agonists and antagonists bound to the same, relatively large, binding site in the receptor, created by residues from transmembrane helices TM2, TM3, TM5, TM6 and TM7 and close to the extra cellular end of the receptor bundle. The key difference between these two types of ligands is interaction with residue Val2836.55 and a flexibility of ligand molecules. Ligands that cannot easily avoid this interaction will initiate movement of the intracellular end of TM6 (by a mechanism which involves Met1343.36 and several aminoacids of TM5) and possibly activate the receptor when assisted by G-protein.

Keywords

Molecular modeling ORL1 receptor Ligand–receptor interactions Docking simulation Molecular dynamics 

Abbreviations

ORL1

Opioid receptor like 1

GPCR

G-protein coupled receptors

NC

Nociceptin

EC2

Second extra cellular loop

EC3

Third extra cellular

IC3

Third intracellular loop

MD

Molecular dynamics

Notes

Acknowledgments

This work was supported by the Ministry of Education and Science of the Republic of Serbia (Grant Nos. OI172032 and OI172035).

Supplementary material

10930_2014_9555_MOESM1_ESM.doc (280 kb)
Supplementary material 1 (DOC 280 kb)
10930_2014_9555_MOESM2_ESM.mpg (3 mb)
Supplementary material 2 (MPG 3048 kb)
10930_2014_9555_MOESM3_ESM.mpg (3.4 mb)
Supplementary material 3 (MPG 3504 kb)
10930_2014_9555_MOESM4_ESM.mpg (3 mb)
Supplementary material 4 (MPG 3073 kb)

References

  1. 1.
    Audet M, Bouvier M (2008) Insights into signaling from the beta2-adrenergic receptor structure. Nat Chem Biol 4:397–403CrossRefGoogle Scholar
  2. 2.
    Barlocco D, Cignarella G, Giardina GA, Toma L (2000) The opioid-receptor-like 1 (ORL-1) as a potential target for new analgesics. Eur J Med Chem 35:275–282CrossRefGoogle Scholar
  3. 3.
    Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O (1995) Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor. Science 270:792–794CrossRefGoogle Scholar
  4. 4.
    Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B, Mazarguil H, Vassart G, Parmentier M, Costentin J (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377(6549):532–535CrossRefGoogle Scholar
  5. 5.
    Zaveri N (2003) Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents. Life Sci 73:663–678CrossRefGoogle Scholar
  6. 6.
    Palin R, Clark JK, Evans L, Feilden H, Fletcher D, Hamilton NM, Houghton AK, Jones PS, McArthur D, Montgomery B, Ratcliffe PD, Smith AR, Sutherland A, Weston MA, Wishart G (2009) Rapid access towards follow-up NOP receptor agonists using a knowledge based approach. Bioorg Med Chem Lett 19(22):6441–6446CrossRefGoogle Scholar
  7. 7.
    Zaveri N, Jiang F, Olsen C, Polgar W, Toll L (2005) Small-molecule agonists and antagonists of the opioid receptor-like receptor (ORL1, NOP): ligand-based analysis of structural factors influencing intrinsic activity at NOP. AAPS J 7(2):E345–E352CrossRefGoogle Scholar
  8. 8.
    Bes B, Meunier JC (2003) Identification of a hexapeptide binding region in the nociceptin (ORL1) receptor by photo-affinity labelling with Ac-Arg-Bpa-Tyr-Arg-Trp-Arg-NH2. Biochem Biophys Res Commun 310:992–1001CrossRefGoogle Scholar
  9. 9.
    Lambert DG (2008) The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 7(8):694–710CrossRefGoogle Scholar
  10. 10.
    Bignan GC, Battista K, Connolly PJ, Orsini MJ, Liu J, Middleton SA, Reitz AB (2006) 3-(4-Piperidinyl) indoles and 3-(4-piperidinyl)pyrrolo-[2,3-b] pyridines as ligands for the ORL-1 receptor. Bioorg Med Chem Lett 16(13):3524–3528CrossRefGoogle Scholar
  11. 11.
    Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC (2012) Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485(7398):395–399CrossRefGoogle Scholar
  12. 12.
    Mollereau C, Mouledous L, Lapalu S, Cambois G, Moisand C, Butour JL, Meunier JC (1999) Distinct mechanisms for activation of the opioid receptor-like 1 and kappa-opioid receptors by nociceptin and dynorphin A. Mol Pharmacol 55(2):324–331Google Scholar
  13. 13.
    Isozaki K, Okada K, Koikawa S, Nose T, Costa T, Shimohigashi Y (2006) Residual roles of hydrophobic amino acids in the fifth transmembrane domain of ORL1 receptor in its activation. Pept Sci 43:11Google Scholar
  14. 14.
    Isozaki K, Li J, Okada K, Nishimura H, Matsushima A, Nose T, Costa T, Shimohigashi Y (2009) Spare interactions of highly potent [Arg(14), Lys(15)] nociceptin for cooperative induction of ORL1 receptor activation. Bioorg Med Chem 17:7904–7908CrossRefGoogle Scholar
  15. 15.
    Akuzawa N, Takeda S, Ishiguro M (2007) Structural modelling and mutation analysis of a nociceptin receptor and its ligand complexes. J Biochem 141(6):907–916CrossRefGoogle Scholar
  16. 16.
    Mouledous L, Topham CM, Mazarguil H, Meunier JC (2000) Direct identification of a peptide binding region in the opioid receptor-like 1 receptor by photoaffinity labeling with [Bpa(10), Tyr(14)] nociceptin. J Biochem 275(38):29268–29274Google Scholar
  17. 17.
    Kam KW, New DC, Wong YH (2002) Constitutive activation of the opioid receptor-like (ORL1) receptor by mutation of Asn133 to tryptophan in the third transmembrane region. J Neurochem 83:1461–1470CrossRefGoogle Scholar
  18. 18.
    Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC (2000) Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain. Mol Pharmacol 57(3):495–502Google Scholar
  19. 19.
    New DC, Wong YH (2002) The ORL1 receptor: molecular pharmacology and signalling mechanisms. Neurosignals 11(4):197–212CrossRefGoogle Scholar
  20. 20.
    Philip AE, Poupaert JH, McCurdy CR (2005) Opioid receptor-like 1 (ORL1) molecular “road map” to understanding ligand interaction and selectivity. Curr Top Med Chem 5(3):325–340CrossRefGoogle Scholar
  21. 21.
    Meng F, Taylor LP, Hoversten MT, Ueda Y, Ardati A, Reinscheid RK, Monsma FJ, Watson SJ, Civelli O, Akil H (1996) Moving from the orphanin FQ receptor to an opioid receptor using four point mutations. J Biol Chem 271(50):32016–32020CrossRefGoogle Scholar
  22. 22.
    Topham CM, Mouledous L, Poda G, Maigret B, Meunier JC (1998) Molecular modeling of the ORL1 receptor and its complex with nociceptin. Protein Eng 11(12):1163–1179CrossRefGoogle Scholar
  23. 23.
    Broer BM, Gurrath M, Holtje HD (2003) Molecular modelling studies on the ORL1-receptor and ORL1-agonists. J Comput Aided Mol Des 17(11):739–754CrossRefGoogle Scholar
  24. 24.
    Huang XQ, Jiang HL, Luo XM, Chen KX, Zhu YC, Ji RY, Cao Y (2000) Comparative molecular modeling on 3-D structure of opioid receptor-like 1 receptor. Acta Pharmacol Sin 21:529–535Google Scholar
  25. 25.
    Mustazza C, Borioni A, Sestili I, Sbraccia M, Rodomonte A, Farretti R, DelGiudice MR (2006) Synthesis and evaluation as NOP ligands of some spiro[piperidine-4,2′(1′H)-quinazolin]-4′(3′H)-ones and spiro[piperidine-4,5′(6′H)-[1,2,4]triazolo[1,5-c]quinazolines]. Chem Pharm Bull 54(5):611–622CrossRefGoogle Scholar
  26. 26.
    Okano M, Mito J, Maruyama Y, Masuda H, Niwa T, Nakagawa S, Nakamura Y, Matsuura A (2009) Discovery and structure-activity relationships of 4-aminoquinazoline derivatives, a novel class of opioid receptor like-1 (ORL1) antagonists. Bioorg Med Chem 17(1):119–132CrossRefGoogle Scholar
  27. 27.
    Liu M, He L, Hu X, Liu P, Luo H (2010) 3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor. Bioorg Med Chem Lett 20(23):7004–7010CrossRefGoogle Scholar
  28. 28.
    Daga PR, Zaveri NT (2012) Homology modeling and molecular dynamics simulations of the active state of the nociceptin receptor reveal new insights into agonist binding and activation. Proteins 80(8):1948–1961Google Scholar
  29. 29.
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High- resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318:1258–1265CrossRefGoogle Scholar
  30. 30.
    Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, DeVree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK (2011) Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature 469:175–180CrossRefGoogle Scholar
  31. 31.
    Valentin-Hansen L, Groenen M, Nygaard R, Frimurer TM, Holliday ND, Schwartz TW (2012) The arginine of the DRY motif in transmembrane segment III functions as a balancing micro-switch in the activation of the β2-adrenergic receptor. J Biol Chem 287(38):31973–319782CrossRefGoogle Scholar
  32. 32.
    Holst B, Nygaard R, Valentin-Hansen L, Bach A, Engelstoft MS, Petersen PS, Frimurer TM, Schwartz TW (2010) A conserved aromatic lock for the tryptophan rotameric switch in TM-VI of seven-transmembrane receptors. J Biol Chem 285(6):3973–3986CrossRefGoogle Scholar
  33. 33.
    Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DA, Rasmussen SG, Choi HJ, DeVree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK (2011) Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature 469:236–240CrossRefGoogle Scholar
  34. 34.
    Vanni S, Rothlisberger U (2012) A closer look into g protein coupled receptor activation: X-ray crystallography and long-scale molecular dynamics simulations. Curr Med Chem 19(8):1135–1145CrossRefGoogle Scholar
  35. 35.
    Vanni S, Neri M, Tavernelli I, Rothlisberger U (2012) Predicting novel binding modes of agonists to b adrenergic receptors using all-atom molecular dynamics simulation. PLoS Comput Biol 7(1):e100105Google Scholar
  36. 36.
    Niv MY, Skrabanek L, Filizola M, Weinstein H (2006) Modeling activated states of GPCRs: the rhodopsin template. J Comput Aided Mol Des 20:437–444CrossRefGoogle Scholar
  37. 37.
    Dror RO, Pan AC, Arlow DH, Borhani DW, Maragakis P, Shan Y, Xu H, Shaw DE (2011) Pathway and mechanism of drug binding to G-protein-coupled receptors. PNAS 108(32):13118–13123CrossRefGoogle Scholar
  38. 38.
    Dror RO, Pan AC, Arlow DH, Maragakis P, Mildorf TJ, Pan AC, Xu H, Borhani DW, Shaw DE (2011) Activation mechanism of the β 2-adrenergic receptor. PNAS 108(46):13118–13123CrossRefGoogle Scholar
  39. 39.
    Dror RO, Green HF, Valant C, Borhani DW, Valcourt JR, Pan AC, Arlow DH, Canals M, Lane JR, Rahmani R, Baell JB, Sexton PM, Christopoulos A, Shaw DE (2013) Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503(7475):295–299Google Scholar
  40. 40.
    Leguebe M, Nguyen C, Capece L, Hoang Z, Giorgetti A, Carloni P (2012) Hybrid molecular mechanics/coarse-grained simulations for structural prediction of G-protein coupled receptor/ligand complexes. PLoS One 7(10):e47332CrossRefGoogle Scholar
  41. 41.
    Marchioni A, Capece L, Giorgetti A, Gasparini P, Behrens M, Carloni P, Meyerhof W (2013) Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding. PLoS One 8(5):e64675CrossRefGoogle Scholar
  42. 42.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802CrossRefGoogle Scholar
  43. 43.
    Humphrey W, Dalke A, Schulten K (1996) VMD-visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  44. 44.
    MacKerell AD Jr, Feig M, Brooks CL (2004) Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem 25:1400–1415CrossRefGoogle Scholar
  45. 45.
    MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE III, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics. Studies of proteins. J Phys Chem B 102:3586–3616CrossRefGoogle Scholar
  46. 46.
    Feller SE, Gawrisch G, MacKerell AD Jr (2002) Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties. J Am Chem Soc 124:318–326CrossRefGoogle Scholar
  47. 47.
    Feller S, MacKerell AD Jr (2000) An improved empirical potential energy function for molecular simulations of phospholipids. J Phys Chem B 104:7510–7515CrossRefGoogle Scholar
  48. 48.
    Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD Jr (2010) CHARMM general force field (CGenFF): a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comb Chem 31:671–690Google Scholar
  49. 49.
    Gaussian 03 (2004) Revision C.02, Gaussian Inc.: Wallingford, CTGoogle Scholar
  50. 50.
    PARADOX cluster at the scientific computing laboratory of the institute of physics Belgrade, supported in part by the Serbian Ministry of Education and Science under project No. ON171017, and by the European Commission under FP7 projects HP-SEE, PRACE-1IP, PRACE-2IP, EGI-InSPIREGoogle Scholar
  51. 51.
    Avogadro: an open-source molecular builder and visualization tool. Version 1.0.0. http://avogadro.Openmolecules.net/ (Accessed January 8, 2014)
  52. 52.
    Stewart JJ (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13(12):1173–1213CrossRefGoogle Scholar
  53. 53.
    MOPAC2009, James J. P. Stewart (2008) Stewart computational chemistry, Colorado Springs, CO, USA, http://OpenMOPAC.net. (Accessed January 8, 2014)
  54. 54.
    Schmidt MW, Baldridge KK, Boatz LA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su S, Windus TL, Dupuis M, Montgomery JA (1993) General atomic and molecular electronic structure system. J Comput Chem 14:1347–1363CrossRefGoogle Scholar
  55. 55.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461Google Scholar
  56. 56.
    Modeling of ORL1 Receptor Ligand Interactions. Chem Pap, in pressGoogle Scholar
  57. 57.
    Wonerow P, Schöneberg T, Schultz G, Gudermann T, Paschke R (1998) Deletions in the third intracellular loop of the thyrotropin receptor: a new mechanism for constitutive activation. J Biol Chem 273(14):7900–7905CrossRefGoogle Scholar
  58. 58.
    Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ (1992) Constitutive activation of the alpha 1b-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. J Biol Chem 267(3):1430–1433Google Scholar
  59. 59.
    Mathew E, Ding F, Naider F, Dumont ME (2013) Functional fusions of T4 lysozyme in the third intracellular loop of a G protein-coupled receptor identified by a random screening approach in yeast. Protein Eng Des Sel 26(1):59–71CrossRefGoogle Scholar
  60. 60.
    Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, Nambu H, Iguchi T, Iwasawa Y, Ohta H (2000) In vitro and in vivo pharmacological characterization of J-113397, potent and selective non-peptidyl ORL1 receptor antagonist. Eur J Pharmacol 402(1–2):45–53CrossRefGoogle Scholar
  61. 61.
    Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debiski A, Filipek S (2012) Action of molecular switches in GPCRs. Curr Med Chem 19:1090–1109CrossRefGoogle Scholar
  62. 62.
    Smith ED, Vinson NA, Zhong D, Berrang BD, Catanzaro JL, Thomas JB, Navarro HA, Gilmour BP, Deschamps J, Carroll FI (2008) A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay. Bioorg Med Chem 16(2):822–829CrossRefGoogle Scholar
  63. 63.
    Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, Kato T, Ohta H, Iwasawa Y (1999) Discovery of the first potent and selective small molecule opioid receptor-like(ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl - 1,3 -dihydro-2H-benzimidazol-2-one(J-113397). J Med Chem 42(25):5061–5063CrossRefGoogle Scholar
  64. 64.
    Zaveri NT, Jiang F, Olsen CM, Deschamps JR, Parrish D, Polgar W, Toll L (2004) A novel series of piperidin-4-yl-1,3-dihydroindol-2-ones as agonist and antagonist ligands at the nociceptin receptor. J Med Chem 47(12):2973–2976CrossRefGoogle Scholar
  65. 65.
    Ho GD, Bercovici A, Tulshian D, Greenlee WJ, Fawzi A, Smith Tothan A, Zhang H (2007) Synthesis and structure–activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: part 1. Bioorg Med Chem Lett 17(11):3023–3027CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Faculty of ChemistryUniversity of BelgradeBelgradeSerbia
  2. 2.ICTM, Center for ChemistryUniversity of BelgradeBelgradeSerbia
  3. 3.Innovation Center of the Faculty of ChemistryUniversity of BelgradeBelgradeSerbia

Personalised recommendations