Computational Drug Discovery and Design pp 595-613

Part of the Methods in Molecular Biology book series (MIMB, volume 819) | Cite as

Homology Modeling of Cannabinoid Receptors: Discovery of Cannabinoid Analogues for Therapeutic Use

  • Chia-en A. Chang
  • Rizi Ai
  • Michael Gutierrez
  • Michael J. Marsella
Protocol

Abstract

Cannabinoids represent a promising class of compounds for developing novel therapeutic agents. Since the isolation and identification of the major psychoactive component Δ9-THC in Cannabis sativa in the 1960s, numerous analogues of the classical plant cannabinoids have been synthesized and tested for their biological activity. These compounds primarily target the cannabinoid receptors 1 (CB1) and Cannabinoid receptors 2 (CB2). This chapter focuses on CB1. Despite the lack of crystal structures for CB1, protein-based homology modeling approaches and molecular docking methods can be used in the design and discovery of cannabinoid analogues. Efficient synthetic approaches for therapeutically interesting cannabinoid analogues have been developed to further facilitate the drug discovery process.

Key words

GPCR Binding Energy calculation Molecular dynamics Agonist 

References

  1. 1.
    Li, H. L. 1974. Origin and Use of Cannabis in Eastern Asia Linguistic-Cultural Implications. Economic Botany 28:293–301.CrossRefGoogle Scholar
  2. 2.
    Mechoulam, R. 1986. Cannabinoids as Therapeutic Agents. CRC Press.Google Scholar
  3. 3.
    Robson, P. 2001. Therapeutic aspects of cannabis and cannabinoids. British Journal of Psychiatry 178:107–115.PubMedCrossRefGoogle Scholar
  4. 4.
    Gaoni, Y., and R. Mechoulam. 1964. ISOLATION STRUCTURE + PARTIAL SYNTHESIS OF ACTIVE CONSTITUENT OF HASHISH. Journal of the American Chemical Society 86:1646-&.Google Scholar
  5. 5.
    Matsuda, L. A., S. J. Lolait, M. J. Brownstein, A. C. Young, and T. I. Bonner. 1990. STRUCTURE OF A CANNABINOID RECEPTOR AND FUNCTIONAL EXPRESSION OF THE CLONED CDNA. Nature 346:561–564.PubMedCrossRefGoogle Scholar
  6. 6.
    Munro, S., K. L. Thomas, and M. Abushaar. 1993. MOLECULAR CHARACTERIZATION OF A PERIPHERAL RECEPTOR FOR CANNABINOIDS. Nature 365:61–65.PubMedCrossRefGoogle Scholar
  7. 7.
    Ashton, J. C., I. Appleton, C. L. Darlington, and P. F. Smith. 2004. Cannabinoid CB1 receptor protein expression in the rat choroid plexus: a possible involvement of cannabinoids in the regulation of cerebrospinal fluid. Neuroscience Letters 364:40–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Pacher, P., S. Batkai, and G. Kunos. 2006. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews 58:389–462.PubMedCrossRefGoogle Scholar
  9. 9.
    Bellocchio, L., G. Mancini, V. Vicennati, R. Pasquali, and U. Pagotto. 2006. Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases. Current Opinion in Pharmacology 6:586–591.PubMedCrossRefGoogle Scholar
  10. 10.
    Steinberg, B. A., and C. P. Cannon. 2007. Cannabinoid-1 receptor blockade in cardiometabolic risk reduction: Safety, tolerability, and therapeutic potential. American Journal of Cardiology 100:27P–32P.PubMedCrossRefGoogle Scholar
  11. 11.
    Kunos, G., and D. Osei-Hyiaman. 2008. Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. American Journal of Physiology-Gastrointestinal and Liver Physiology 294:G1101–G1104.PubMedCrossRefGoogle Scholar
  12. 12.
    Ross, R. A. 2007. Allosterism and cannabinoid CB1 receptors: the shape of things to come. Trends in Pharmacological Sciences 28:567–572.PubMedCrossRefGoogle Scholar
  13. 13.
    Begg, M., P. Pacher, S. Batkai, D. Osei-Hyiaman, L. Offertaler, F. M. Mo, H. Liu, and G. Kunos. 2005. Evidence for novel cannabinoid receptors. Pharmacology & Therapeutics 106:133–145.CrossRefGoogle Scholar
  14. 14.
    Harkany, T., M. Guzman, I. Galve-Roperh, P. Berghuis, L. A. Devi, and K. Mackie. 2007. The emerging functions of endocannabinoid signaling during CNS development. Trends in Pharmacological Sciences 28:83–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Pertwee, R. G. 2005. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. Aaps Journal 7:E625–E654.PubMedCrossRefGoogle Scholar
  16. 16.
    Howlett, A. C. 2002. The cannabinoid receptors. Prostaglandins & Other Lipid Mediators 68-9:619–631.CrossRefGoogle Scholar
  17. 17.
    Palczewski, K., T. Kumasaka, T. Hori, C. A. Behnke, H. Motoshima, B. A. Fox, I. Le Trong, D. C. Teller, T. Okada, R. E. Stenkamp, M. Yamamoto, and M. Miyano. 2000. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745.PubMedCrossRefGoogle Scholar
  18. 18.
    Park, J. H., P. Scheerer, K. P. Hofmann, H. W. Choe, and O. P. Ernst. 2008. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454:183–U133.PubMedCrossRefGoogle Scholar
  19. 19.
    Murakami, M., and T. Kouyama. 2008. Crystal structure of squid rhodopsin. Nature 453:363–U333.PubMedCrossRefGoogle Scholar
  20. 20.
    Wacker, D., G. Fenalti, M. A. Brown, V. Katritch, R. Abagyan, V. Cherezov, and R. C. Stevens. 2010. Conserved Binding Mode of Human beta(2) Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography.Google Scholar
  21. 21.
    Bokoch, M. P., Y. Z. Zou, S. G. F. Rasmussen, C. W. Liu, R. Nygaard, D. M. Rosenbaum, J. J. Fung, H. J. Choi, F. S. Thian, T. S. Kobilka, J. D. Puglisi, W. I. Weis, L. Pardo, R. S. Prosser, L. Mueller, and B. K. Kobilka. 2010. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.Google Scholar
  22. 22.
    Jaakola, V. P., M. T. Griffith, M. A. Hanson, V. Cherezov, E. Y. T. Chien, J. R. Lane, A. P. Ijzerman, and R. C. Stevens. 2008. The 2.6 Angstrom Crystal Structure of a Human A(2A) Adenosine Receptor Bound to an Antagonist. Science 322:1211–1217.PubMedCrossRefGoogle Scholar
  23. 23.
    Warne, T., M. J. Serrano-Vega, J. G. Baker, R. Moukhametzianov, P. C. Edwards, R. Henderson, A. G. W. Leslie, C. G. Tate, and G. F. X. Schertler. 2008. Structure of a beta(1)-adrenergic G-protein-coupled receptor.Google Scholar
  24. 24.
    Scheerer, P., J. H. Park, P. W. Hildebrand, Y. J. Kim, N. Krauss, H. W. Choe, K. P. Hofmann, and O. P. Ernst. 2008. Crystal structure of opsin in its G-protein-interacting conformation.Google Scholar
  25. 25.
    Wu, B., E. Y. Chien, C. D. Mol, G. Fenalti, W. Liu, V. Katritch, R. Abagyan, A. Brooun, P. Wells, F. C. Bi, D. J. Hamel, P. Kuhn, T. M. Handel, V. Cherezov, and R. C. Stevens. 2010. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.Google Scholar
  26. 26.
    Mobarec, J. C., R. Sanchez, and M. Filizola. 2009. Modern Homology Modeling of G-Protein Coupled Receptors: Which Structural Template to Use? Journal of Medicinal Chemistry 52:5207–5216.PubMedCrossRefGoogle Scholar
  27. 27.
    Schwartz, T. W., and W. L. Hubbell. 2008. Structural biology - A moving story of receptors. Nature 455:473–474.PubMedCrossRefGoogle Scholar
  28. 28.
    Mechoulam, R. 1973. Marijuana. Chemistry Metabolism, Pharmacology and Clinical Effects. Academic Press, New York.Google Scholar
  29. 29.
    Taylor, E. C., K. Lenard, and Y. Shvo. 1966. ACTIVE CONSTITUENTS OF HASHISH. SYNTHESIS OF DL-DELTA6-3,4-TRANS-TETRAHYDROCANNABINOL. Journal of the American Chemical Society 88:367-&.Google Scholar
  30. 30.
    Mechoula.R, P. Braun, and Y. Gaoni. 1972. SYNTHESES OF DELTA-TETRAHYDROCANNABINOL AND RELATED CANNABINOIDS. Journal of the American Chemical Society 94:6159-&.Google Scholar
  31. 31.
    Evans, D. A., E. A. Shaughnessy, and D. M. Barnes. 1997. Cationic bis(oxazoline)Cu(II) Lewis acid catalysts. Application to the asymmetric synthesis of ent-Delta(1)-tetrahydrocannabinol. Tetrahedron Letters 38:3193–3194.CrossRefGoogle Scholar
  32. 32.
    Trost, B. M., and K. Dogra. 2007. Synthesis of (-)-Delta(9)-trans-Tetrahydrocannabinol: Stereocontrol via Mo-catalyzed asymmetric allylic alkylation reaction. Organic Letters 9:861–863.PubMedCrossRefGoogle Scholar
  33. 33.
    Arnold, K., L. Bordoli, J. Kopp, and T. Schwede. 2006. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.Google Scholar
  34. 34.
    Kiefer, F., K. Arnold, M. Kunzli, L. Bordoli, and T. Schwede. 2009. The SWISS-MODEL Repository and associated resources.Google Scholar
  35. 35.
    Peitsch, M. C. 1995. Protein Modeling by E-Mail (Vol 13, Pg 658, 1995).Google Scholar
  36. 36.
    N. Eswar, M. A. M.-R., B. Webb, M. S. Madhusudhan, D. Eramian, M. Shen, U. Pieper, A. Sali. 2006. Comparative Protein Structure Modeling With MODELLER. John Wiley & Sons, Inc.Google Scholar
  37. 37.
    Guex, N., and M. C. Peitsch. 1997. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling.Google Scholar
  38. 38.
    Case, D. A., T. E. Cheatham, T. Darden, H. Gohlke, R. Luo, K. M. Merz, A. Onufriev, C. Simmerling, B. Wang, and R. J. Woods. 2005. The Amber biomolecular simulation programs.Google Scholar
  39. 39.
    Brooks, B. R., C. L. Brooks, A. D. Mackerell, L. Nilsson, R. J. Petrella, B. Roux, Y. Won, G. Archontis, C. Bartels, S. Boresch, A. Caflisch, L. Caves, Q. Cui, A. R. Dinner, M. Feig, S. Fischer, J. Gao, M. Hodoscek, W. Im, K. Kuczera, T. Lazaridis, J. Ma, V. Ovchinnikov, E. Paci, R. W. Pastor, C. B. Post, J. Z. Pu, M. Schaefer, B. Tidor, R. M. Venable, H. L. Woodcock, X. Wu, W. Yang, D. M. York, and M. Karplus. 2009. CHARMM: The Biomolecular Simulation Program.Google Scholar
  40. 40.
    Van der Spoel, D., E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, and H. J. C. Berendsen. 2005. GROMACS: Fast, flexible, and free.Google Scholar
  41. 41.
    Phillips, J. C., R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot, R. D. Skeel, L. Kale, and K. Schulten. 2005. Scalable molecular dynamics with NAMD. Journal of Computational Chemistry 26:1781–1802.PubMedCrossRefGoogle Scholar
  42. 42.
    Humphrey, W., A. Dalke, and K. Schulten. 1996. VMD: Visual molecular dynamics. Journal of Molecular Graphics 14:33-&.Google Scholar
  43. 43.
    Still, W. C., M. Kahn, and A. Mitra. 1978. RAPID CHROMATOGRAPHIC TECHNIQUE FOR PREPARATIVE SEPARATIONS WITH MODERATE RESOLUTION. Journal of Organic Chemistry 43:2923–2925.CrossRefGoogle Scholar
  44. 44.
    Altschul, S. F., T. L. Madden, A. A. Schaffer, J. H. Zhang, Z. Zhang, W. Miller, and D. J. Lipman. 1997. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.Google Scholar
  45. 45.
    Soding, J. 2005. Protein homology detection by HMM-HMM comparison (vol 21, pg 951, 2005).Google Scholar
  46. 46.
    Forrest, L. R., C. L. Tang, and B. Honig. 2006. On the accuracy of homology modeling and sequence alignment methods applied to membrane proteins. Biophysical Journal 91:508–517.PubMedCrossRefGoogle Scholar
  47. 47.
    Notredame, C., D. G. Higgins, and J. Heringa. 2000. T-Coffee: A novel method for fast and accurate multiple sequence alignment. Journal of Molecular Biology 302:205–217.PubMedCrossRefGoogle Scholar
  48. 48.
    Thompson, J. D., D. G. Higgins, and T. J. Gibson. 1994. CLUSTAL-W - IMPROVING THE SENSITIVITY OF PROGRESSIVE MULTIPLE SEQUENCE ALIGNMENT THROUGH SEQUENCE WEIGHTING, POSITION-SPECIFIC GAP PENALTIES AND WEIGHT MATRIX CHOICE. Nucleic Acids Research 22:4673–4680.PubMedCrossRefGoogle Scholar
  49. 49.
    Torda, A. E., J. B. Procter, and T. Huber. 2004. Wurst: a protein threading server with a structural scoring function, sequence profiles and optimized substitution matrices.Google Scholar
  50. 50.
    Krivov, G. G., M. V. Shapovalov, and R. L. Dunbrack. 2009. Improved prediction of protein side-chain conformations with SCWRL4.Google Scholar
  51. 51.
    Lu, M. Y., A. D. Dousis, and J. P. Ma. 2008. OPUS-Rota: A fast and accurate method for side-chain modeling. Protein Science 17:1576–1585.PubMedCrossRefGoogle Scholar
  52. 52.
    Laskowski, R. A., M. W. Macarthur, D. S. Moss, and J. M. Thornton. 1993. Procheck - a Program to Check the Stereochemical Quality of Protein Structures.Google Scholar
  53. 53.
    Hooft, R. W. W., G. Vriend, C. Sander, and E. E. Abola. 1996. Errors in protein structures.Google Scholar
  54. 54.
    Benkert, P., S. C. E. Tosatto, and D. Schomburg. 2008. QMEAN: A comprehensive scoring function for model quality assessment.Google Scholar
  55. 55.
    Shim, J. Y. 2009. Transmembrane Helical Domain of the Cannabinoid CB1 Receptor. Biophysical Journal 96:3251–3262.PubMedCrossRefGoogle Scholar
  56. 56.
    Lang, P. T., S. R. Brozell, S. Mukherjee, E. F. Pettersen, E. C. Meng, V. Thomas, R. C. Rizzo, D. A. Case, T. L. James, and I. D. Kuntz. 2009. DOCK 6: Combining techniques to model RNA-small molecule complexes. Rna-a Publication of the Rna Society 15:1219–1230.CrossRefGoogle Scholar
  57. 57.
    Osterberg, F., G. M. Morris, M. F. Sanner, A. J. Olson, and D. S. Goodsell. 2002. Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins-Structure Function and Bioinformatics 46:34–40.CrossRefGoogle Scholar
  58. 58.
    Feher, M. 2006. Consensus scoring for protein-ligand interactions. Drug Discovery Today 11:421–428.PubMedCrossRefGoogle Scholar
  59. 59.
    Morris, G. M., D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart, R. K. Belew, and A. J. Olson. 1998. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry 19:1639–1662.CrossRefGoogle Scholar
  60. 60.
    Chang, C. E., and M. K. Gilson. 2003. Tork: Conformational analysis method for molecules and complexes. Journal of Computational Chemistry 24:1987–1998.PubMedCrossRefGoogle Scholar
  61. 61.
    Razdan, R. K., H. C. Dalzell, and G. R. Handrick. 1974. HASHISH.10. SIMPLE ONE-STEP SYNTHESIS OF (-)-TETRAHYDROCANNABINOL (THC) FROM PARA-MENTHA-2,8-DIEN-1-OL AND OLIVETOL. Journal of the American Chemical Society 96:5860–5865.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Chia-en A. Chang
    • 1
  • Rizi Ai
    • 1
  • Michael Gutierrez
    • 1
  • Michael J. Marsella
    • 2
  1. 1.Department of ChemistryUniversity of CaliforniaRiversideUSA
  2. 2.Department of ChemistryUniversity of California at RiversideRiversideUSA

Personalised recommendations