Skip to main content
SpringerLink
Log in

In silico investigation of interactions between human cannabinoid receptor-1 and its antagonists

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Cannabinoid receptor-1 (CB1) is widely expressed in the central nervous system and plays a vital role in regulating food intake and energy expenditure. CB1 antagonists such as Rimonabant have been used in clinic to inhibit food intake, and therefore reduce body weight in obese animals and humans. To investigate the binding modes of CB1 antagonists to the receptor, both receptor- and ligand-based methods were implemented in this study. At first, a pharmacophore model was generated based on 31 diverse CB1 antagonists collected from literature. A test set validation and a simulated virtual screening evaluation were then performed to verify the reliability and discriminating ability of the pharmacophore. Meanwhile, the homology model of CB1 receptor was constructed based on the crystal structure of human β 2 adrenergic receptor (β 2-AR). Several classical antagonists were then docked into the optimized homology model with induced fit docking method. A hydrogen bond between the antagonists and Lys192 on the third transmembrane helix of the receptor was formed in the docking study, which has proven to be critical for receptor-ligand interaction by biological experiments. The structure obtained from induced fit docking was then confirmed to be a reliable model for molecular docking from the result of the simulated virtual screening. The consistency between the pharmacophore and the homology structure further proved the previous observation. The built receptor structure and antagonists’ pharmacophore should be useful for the understanding of inhibitory mechanism and development of novel CB1 antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 98(7):3662–3665. doi:10.1073/pnas.061029898

    Article  CAS  Google Scholar 

  2. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54(2):161–202

    Article  CAS  Google Scholar 

  3. Boyd ST (2006) The endocannabinoid system. Pharmacotherapy 26(12 Pt 2):218S–221S. doi:10.1592/phco.26.12part2.218S

    Article  CAS  Google Scholar 

  4. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564. doi:10.1038/346561a0

    Article  CAS  Google Scholar 

  5. Lu ZL, Saldanha JW, Hulme EC (2002) Seven-transmembrane receptors: crystals clarify. Trends Pharmacol Sci 23(3):140–146

    Article  CAS  Google Scholar 

  6. James PT, Leach R, Kalamara E, Shayeghi M (2001) The worldwide obesity epidemic. Obes Res 9:228s–233s

    Article  Google Scholar 

  7. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337(9):581–588

    Article  CAS  Google Scholar 

  8. Woods SC (2007) Role of the endocannabinoid system in regulating cardiovascular and metabolic risk factors. Am J Med 120(3 Suppl 1):S19–S25. doi:10.1016/j.amjmed.2007.01.004

    Article  CAS  Google Scholar 

  9. Carai MA, Colombo G, Gessa GL (2005) Rimonabant: the first therapeutically relevant cannabinoid antagonist. Life Sci 77(19):2339–2350. doi:10.1016/j.lfs.2005.04.017

    Article  CAS  Google Scholar 

  10. Wang HW, Duffy RA, Boykow GC, Chackalamannil S, Madison VS (2008) Identification of novel cannabinoid CB1 receptor antagonists by using virtual screening with a pharmacophore model. J Med Chem 51(8):2439–2446. doi:10.1021/Jm701519h

    Article  CAS  Google Scholar 

  11. Murineddu G, Ruiu S, Loriga G, Manca I, Lazzari P, Reali R, Pani L, Toma L, Pinna GA (2005) Tricyclic pyrazoles. 3. Synthesis, biological evaluation, and molecular modeling of analogues of the cannabinoid antagonist 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo [6, 7]cyclohepta[1,2-c]pyrazole-3-carboxamide. J Med Chem 48(23):7351–7362. doi:10.1021/jm050317f

    Article  CAS  Google Scholar 

  12. Krishnamurthy M, Li W, Moore BM (2004) Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands. Bioorg Med Chem 12(2):393–404. doi:10.1016/j.bmc.2003.10.045

    Article  CAS  Google Scholar 

  13. Katoch-Rouse R, Pavlova OA, Caulder T, Hoffman AF, Mukhin AG, Horti AG (2003) Synthesis, structure-activity relationship, and evaluation of SR141716 analogues: Development of central cannabinoid receptor ligands with lower lipophilicity. J Med Chem 46(4):642–645. doi:10.1021/Jm020157x

    Article  CAS  Google Scholar 

  14. Shu H, Izenwasser S, Wade D, Stevens ED, Trudell ML (2009) Synthesis and CB1 cannabinoid receptor affinity of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles. Bioorg Med Chem Lett 19(3):891–893. doi:10.1016/j.bmcl.2008.11.110

    Article  CAS  Google Scholar 

  15. Muccioli GG, Martin D, Scriba GKE, Poppitz W, Poupaert JH, Wouters J, Lambert DM (2005) Substituted 5,5 '-diphenyl-2-thioxoimidazolidin-4-one as CB1 cannabinoid receptor ligands: Synthesis and pharmacological evaluation. J Med Chem 48(7):2509–2517. doi:10.1021/Jm049263k

    Article  CAS  Google Scholar 

  16. Lan RX, Liu Q, Fan PS, Lin SY, Fernando SR, McCallion D, Pertwee R, Makriyannis A (1999) Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42(4):769–776

    Article  CAS  Google Scholar 

  17. Carpino PA, Griffith DA, Sakya S, Dow RL, Black SC, Hadcock JR, Iredale PA, Scott DO, Fichtner MW, Rose CR, Day R, Dibrino J, Butler M, DeBartolo DB, Dutcher D, Gautreau D, Lizano JS, O'Connor RE, Sands MA, Kelly-Sullivan D, Ward KM (2006) New bicyclic cannabinoid receptor-1 (CB1-R) antagonists. Bioorg Med Chem Lett 16(3):731–736. doi:10.1016/j.bmcl.2005.10.019

    Article  CAS  Google Scholar 

  18. Ellsworth BA, Wang Y, Zhu YH, Pendri A, Gerritz SW, Sun C, Carlson KE, Kang LY, Baska RA, Yang YF, Huang Q, Burford NT, Cullen MJ, Johnghar S, Behnia K, Pelleymounter MA, Washburn WN, Ewing WR (2007) Discovery of pyrazine carboxamide CB1 antagonists: The introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series. Bioorg Med Chem Lett 17(14):3978–3982. doi:10.1016/j.bmcl.2007.04.087

    Article  CAS  Google Scholar 

  19. Foloppe N, Benwell K, Brooks TD, Kennett G, Knight AR, Misra A, Monck NJT (2009) Discovery and functional evaluation of diverse novel human CB1 receptor ligands. Bioorg Med Chem Lett 19(15):4183–4190. doi:10.1016/j.bmcl.2009.05.114

    Article  CAS  Google Scholar 

  20. Smith RA, Fathi Z, Brown SE, Choi S, Fan J, Jenkins S, Kluender HC, Konkar A, Lavoie R, Mays R, Natoli J, O'Connor SJ, Ortiz AA, Podlogar B, Taing C, Tomlinson S, Tritto T, Zhang Z (2007) Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives. Bioorg Med Chem Lett 17(3):673–678. doi:10.1016/j.bmcl.2006.10.095

    Article  CAS  Google Scholar 

  21. Lange JH, Kruse CG (2008) Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives. Chem Rec 8(3):156–168. doi:10.1002/tcr.20147

    Article  CAS  Google Scholar 

  22. Griffith DA, Hadcock JR, Black SC, Iredale PA, Carpino PA, DaSilva-Jardine P, Day R, DiBrino J, Dow RL, Landis MS, O'Connor RE, Scott DO (2009) Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperi dine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J Med Chem 52(2):234–237. doi:10.1021/jm8012932 10.1021/jm8012932

    Article  CAS  Google Scholar 

  23. Dow RL, Carpino PA, Hadcock JR, Black SC, Iredale PA, DaSilva-Jardine P, Schneider SR, Paight ES, Griffith DA, Scott DO, O'Connor RE, Nduaka CI (2009) Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2 H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. J Med Chem 52(9):2652–2655. doi:10.1021/jm900255t

    Article  CAS  Google Scholar 

  24. Hurst DP, Lynch DL, Barnett-Norris J, Hyatt SM, Seltzman HH, Zhong M, Song ZH, Nie JJ, Lewis D, Reggio PH (2002) N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor. Mol Pharmacol 62(6):1274–1287

    Article  CAS  Google Scholar 

  25. Hurst D, Umejiego U, Lynch D, Seltzman H, Hyatt S, Roche M, McAllister S, Fleischer D, Kapur A, Abood M, Shi SP, Jones J, Lewis D, Reggio P (2006) Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: Importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. J Med Chem 49(20):5969–5987. doi:10.1021/Jm060446b

    Article  CAS  Google Scholar 

  26. Shire D, Calandra B, Delpech M, Dumont X, Kaghad M, Le Fur G, Caput D, Ferrara P (1996) Structural features of the central cannabinoid CB1 receptor involved in the binding of the specific CB1 antagonist SR 141716A. J Biol Chem 271(12):6941–6946

    Article  CAS  Google Scholar 

  27. Trillou CR, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284(2):R345–R353. doi:10.1152/ajpregu.00545.2002

    CAS  Google Scholar 

  28. Hagmann WK (2008) The discovery of taranabant, a selective cannabinoid-1 receptor inverse agonist for the treatment of obesity. Archiv Der Pharmazie 341(7):405–411. doi:10.1002/ardp. 200700255

    Article  CAS  Google Scholar 

  29. Shim JY, Welsh WJ, Cartier E, Edwards JL, Howlett AC (2002) Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. J Med Chem 45(7):1447–1459

    Article  CAS  Google Scholar 

  30. Tong WD, Hong HX, Xie Q, Shi LM, Fang H, Perkins R (2005) Assessing QSAR Limitations - A Regulatory Perspective. Curr Comput Aid Drug 1(2):195–205

    Article  CAS  Google Scholar 

  31. Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK (2011) Ligand discovery from a dopamine D(3) receptor homology model and crystal structure. Nat Chem Biol 7(11):769–778. doi:10.1038/Nchembio.662

    Article  CAS  Google Scholar 

  32. Sun XQ, Li YZ, Li WH, Xu ZJ, Tang Y (2011) Computational investigation of interactions between human H(2) receptor and its agonists. J Mol Graph Model 29(5):693–701. doi:10.1016/j.jmgm.2010.12.001

    Article  CAS  Google Scholar 

  33. Cheng FX, Xu ZJ, Liu GX, Tang Y (2010) Insights into binding modes of adenosine A(2B) antagonists with ligand-based and receptor-based methods. European Journal of Medicinal Chemistry 45(8):3459–3471. doi:10.1016/j.ejmech.2010.04.039

    Article  CAS  Google Scholar 

  34. Cheng JX, Liu GX, Zhang J, Xu ZJ, Tang Y (2011) Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods. J Mol Model 17(3):477–493. doi:10.1007/s00894-010-0745-1

    Article  CAS  Google Scholar 

  35. Lu C, Jin F, Li C, Li W, Liu G, Tang Y (2011) Insights into binding modes of 5-HT2c receptor antagonists with ligand-based and receptor-based methods. J Mol Model 17(10):2513–2523. doi:10.1007/s00894-010-0936-9

    Article  CAS  Google Scholar 

  36. Jin F, Lu C, Sun X, Li W, Liu G, Tang Y (2011) Insights into the binding modes of human beta-adrenergic receptor agonists with ligand-based and receptor-based methods. Mol Divers 15(4):817–831. doi:10.1007/s11030-011-9311-8

    Article  CAS  Google Scholar 

  37. 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(5854):1258–1265. doi:10.1126/science.1150577

    Article  CAS  Google Scholar 

  38. Shim JY, Welsh WJ, Howlett AC (2003) Homology model of the CB1 cannabinoid receptor: Sites critical for nonclassical cannabinoid agonist interaction. Biopolymers 71(2):169–189. doi:10.1002/Bip. 10424

    Article  CAS  Google Scholar 

  39. Salo OM, Lahtela-Kakkonen M, Gynther J, Jarvinen T, Poso A (2004) Development of a 3D model for the human cannabinoid CB1 receptor. J Med Chem 47(12):3048–3057. doi:10.1021/jm031052c

    Article  CAS  Google Scholar 

  40. Montero C, Campillo NE, Goya P, Paez JA (2005) Homology models of the cannabinoid CB1 and CB2 receptors. A docking analysis study. Eur J Med Chem 40(1):75–83. doi:10.1016/j.ejmech.2004.10.002

    Article  CAS  Google Scholar 

  41. Lin LS, Ha S, Ball RG, Tsou NN, Castonguay LA, Doss GA, Fong TM, Shen CP, Xiao JC, Goulet MT, Hagmann WK (2008) Conformational analysis and receptor docking of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (taranabant, MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist. J Med Chem 51(7):2108–2114. doi:10.1021/Jm7014974

    Article  CAS  Google Scholar 

  42. Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V (2004) The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol 342(2):571–583. doi:10.1016/j.jmb.2004.07.044

    Article  CAS  Google Scholar 

  43. Shim JY (2009) Transmembrane Helical Domain of the Cannabinoid CB1 Receptor. Biophys J 96(8):3251–3262. doi:10.1016/j.bpj.2008.12.3934

    Article  CAS  Google Scholar 

  44. Zhang Y, Burgess JP, Brackeen M, Gilliam A, Mascarella SW, Page K, Seltzman HH, Thomas BF (2008) Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations. J Med Chem 51(12):3526–3539. doi:10.1021/jm8000778

    Article  CAS  Google Scholar 

  45. Catalyst User Guide, version 4.10 (Software Package), Accelrys, Inc, San Diego, CA, USA, 2005. http://accelrys.com/

  46. Accelrys Software Inc., Discovery Studio Modeling Environment, Release 2.1,Accelrys, Inc, San Diego, CA, USA, 2004, http://accelrys.com/

  47. Fang J, Shen J, Cheng FX, Xu ZJ, Liu GX, Tang Y (2011) Computational Insights into Ligand Selectivity of Estrogen Receptors from Pharmacophore Modeling. Mol Inform 30(6–7):539–549. doi:10.1002/minf.201000170

    Article  CAS  Google Scholar 

  48. Boeckmann B, Bairoch A, Apweiler R, Blatter MC, Estreicher A, Gasteiger E, Martin MJ, Michoud K, O'Donovan C, Phan I, Pilbout S, Schneider M (2003) The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res 31(1):365–370

    Article  CAS  Google Scholar 

  49. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242

    Article  CAS  Google Scholar 

  50. Schrödinger LLC (2008) Maestro, version 8.5, Schrödinger, LLC, New York, NY

  51. Gross M (2011) Anarchy in the proteome. Chemistry World, Aug 2011, www.chemistryworld.org

  52. Schrödinger LLC (2008) MacroModel, version 9.6, Schrödinger, LLC, New York, NY

  53. Morris AL, MacArthur MW, Hutchinson EG, Thornton JM (1992) Stereochemical quality of protein structure coordinates. Proteins 12(4):345–364. doi:10.1002/prot.340120407

    Article  CAS  Google Scholar 

  54. Schrödinger LLC (2005) LigPrep version 2.2, Schrödinger, LLC, New York, NY

  55. Schrödinger LLC (2008) Glide version 5.0, Schrödinger, LLC, New York, NY

  56. Wears RL, Lewis RJ (1999) Statistical models and Occam's razor. Acad Emerg Med 6(2):93–94

    Article  CAS  Google Scholar 

  57. Kirchmair J, Markt P, Distinto S, Wolber G, Langer T (2008) Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection - What can we learn from earlier mistakes? J Comput Aided Mol Des 22:213–228

    Article  CAS  Google Scholar 

  58. Jain AN, Nicholls A (2008) Recommendations for evaluation of computational methods. J ComputAided Mol Des 22:133–139

    Article  CAS  Google Scholar 

  59. Telvekar VN, Patel KN (2011) Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, Dihydroxypyrimidines, and bicyclic pyrimidinones. Chem Biol Drug Des 78(1):150–160. doi:10.1111/j.1747-0285.2011.01130.x

    Article  CAS  Google Scholar 

  60. Weber KC, de Lima EF, de Mello PH, da Silva ABF, Honorio KM (2010) Insights into the Molecular Requirements for the Anti-obesity Activity of a Series of CB1 Ligands. Chem Biol Drug Des 76(4):320–329. doi:10.1111/j.1747-0285.2010.01016.x

    Article  CAS  Google Scholar 

  61. Baldwin JM, Schertler GF, Unger VM (1997) An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J Mol Biol 272(1):144–164. doi:10.1006/jmbi.1997.1240

    Article  CAS  Google Scholar 

  62. McAllister SD, Rizvi G, Anavi-Goffer S, Hurst DP, Barnett-Norris J, Lynch DL, Reggio PH, Abood ME (2003) An aromatic microdomain at the cannabinoid CB1 receptor constitutes an agonist/inverse agonist binding region. J Med Chem 46(24):5139–5152. doi:10.1021/Jm0302647

    Article  CAS  Google Scholar 

  63. Kim KH, Kim ND, Seong BL (2010) Pharmacophore-based virtual screening: a review of recent applications. Expert Opin Drug Dis 5(3):205–222. doi:10.1517/17460441003592072

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Program for New Century Excellent Talents in University (Grant NCET-08-0774), the 863 High-Tech Project (Grant 2006AA020404), the 111 Project (Grant B07023), and the Shanghai Committee of Science and Technology (Grant 11DZ2260600).

Author information

Authors and Affiliations

  1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China

    Guanglin Kuang, Guoping Hu, Xianqiang Sun, Weihua Li, Guixia Liu & Yun Tang

Authors
  1. Guanglin Kuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guoping Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xianqiang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weihua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guixia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun Tang.

Supplementary material available

The following information was provided in the Supporting Information: (1) Homology structure of CB1 receptor aligned with β 2-AR; (2) Ramachandran plot of the CB1 homology model; (3) Binding mode of SLV 319 with the homology model; (4) Structures and activities of test set compounds.

(DOC 1304 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuang, G., Hu, G., Sun, X. et al. In silico investigation of interactions between human cannabinoid receptor-1 and its antagonists. J Mol Model 18, 3831–3845 (2012). https://doi.org/10.1007/s00894-012-1381-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1381-8

Keyword

Search

Navigation