Current Science

Open Access Open Access  Restricted Access Subscription Access

Computational Insights into the Agonist Activity of Cannabinoid Receptor Type-2 Ligands Using Molecular Dynamics Simulation


Affiliations
1 Department of Chemistry, School of Advanced Sciences and Languages, VIT Bhopal University, Bhopal 466 114, India
 

Cannabinoid (CB) receptors belong to the G protein-coupled receptor (GPCR) family and were activated by endogenous, phytogenic and synthetic modulators. The CB receptors are involved in a variety of physiological processes, including appetite, pain sensation, mood, memory, etc. The potency of ligands with receptors provides the path through which the latter show agonist, antagonist, or inverse agonist behaviour. Due to the unavailability of crystal structure of CB type-2 (CB2) receptor, we used multiple template comparative homology modelling algorithms to construct 3D models for the same. We performed docking and molecular dynamics simulation study of four synthetic drugs in both cannabinoid type-1 (CB1) and CB2 receptors. These ligands show agonist activity with the CB2 receptor and activates it completely. The results are compared with the CB1 receptor. Molecular properties of the ligands, including molecular, polar and solvent-accessible surface areas, and intramolecular hydrogen bonds were evaluated using molecular dynamics simulations. Our finding demonstrates that the ligand AM-1221 shows the highest binding affinity (–12.73 k cal/mol), whereas UR-144 shows the lowest (–9.83 k cal/mol) towards the CB2 receptor. These findings should stimulate the design of ligands with distinct pharmacological properties associated with the CB2 receptor.

Keywords

Agonist Activity, Cannabinoid Receptors, Induced Fit Docking, Ligands, Molecular Dynamics Simulations.
User
Notifications
Font Size

  • Edery, H., Grunfeld, Y., Ben-Zvi, Z. and Mechoulam, R., Structural requirements for cannabinoid activity. Ann. N.Y. Acad. Sci., 1971, 191, 40–53.

  • Gaoni, Y. and Mechoulam, R., Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc., 1964, 86, 1646–1647.

  • Martin, B. R., Balster, R. L., Razdan, R. K., Harris, L. S. and Dewey, W. L., Behavioral comparisons of the stereoisomers of tetrahydrocannabinols. Life Sci., 1981, 29, 565–574.

  • Lambert, D. M. and Fowler, C. J., The endocannabinoid system: drug targets, lead compounds and potential therapeutic applications. J. Med. Chem., 2005, 48(16), 5059–5087.

  • Pertwee, R. (ed.), Cannabinoids, Springer-Verlag, 2005, p. 2.

  • Galiegue, S. et al., Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem., 1995, 232(1), 54–61.

  • Hanson, M. A. et al., Crystal structure of a lipid G protein-coupled receptor. Science, 2012, 335, 851–855.

  • Wu, H. et al., Structure of the human-opioid receptor in complex with JDTic. Nature, 2012, 485, 327–332.

  • Manglik, A. et al., Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature, 2012, 485, 321–326.

  • Wang, C. et al., Structural basis for molecular recognition at serotonin receptors. Science, 2013, 340, 610–614.

  • Pacher, P. and Mechoulam, R., Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog. Lipid Res., 2011, 50(2), 193–211.

  • Ashton, J. C. et al., Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonist. Curr. Med. Chem., 2008, 15, 1428–1443.

  • Huffman, J. W. and Marriott, K. S. C., Recent advances in the development of selective ligands for the cannabinoid CB2 receptor. Curr. Top. Med. Chem., 2008, 8, 187–204.

  • Benito, C. et al., Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci., 2003, 23(35), 11136–11141.

  • Fernandez-Ruiz, J., Pazos, M. R., García-Arencibia, M., Sagredo, O. and Ramos, J. A., Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol. Cell. Endocrinol., 2008, 286, S91–S96.

  • Tolon, R. M. et al., The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res., 2009, 1283(11), 148–154.

  • Tabrizi, M. A., Baraldi, P. G., Borea, P. A. and Varani, K., Medicinal chemistry, pharmacology and potential therapeutic benefits of cannabinoid CB2 receptor agonist. Chem. Rev., 2016, 116, 519– 560.

  • Baraldi, P. G. et al., 7-oxo-[1,4]oxazino[2,3,4-Ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. J. Med. Chem., 2012, 55(14), 6608–6623.

  • Aghazadeh, T. M. et al., Design, synthesis and pharmacological properties of new heteroarylpyri-dine/heteroarylpyrimidine derivatives as CB(2) cannabinoid receptor partial agonists. J. Med. Chem., 2013, 56(3), 1098–1112.

  • Aghazadeh, T. M. et al., Discovery of 7-oxopyrazolo[1,5-A]pyrimidine6-carboxamides as potent and selective CB(2) cannabinoid receptor inverse agonists. J. Med. Chem., 2013, 56(11), 4482– 4496.

  • Ibrahim, M. M. et al., Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl. Acad. Sci. USA, 2003, 100, 10529–10533.

  • Valenzano, K. J. et al., Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology, 2005, 48, 658–672.

  • Rice, A. S., Farquhar-Smith, W. P. and Nagy, I., Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot. Essent. Fatty Acids, 2002, 66, 243–256.

  • Richardson, J. D., Aanonsen, L. and Hargreaves, K. M. Antihyperalgesic effects of spinal cannabinoids. Eur. J. Pharmacol., 1998, 345, 145–153.

  • http://www.hhs.gov/ash/oah/adolescent-health-topics/substance-abuse/ illicit-and-non-drug-use.html

  • Fernandez-Ruiz, J., Pazos, M. R., García-Arencibia, M., Sagredo, O. and Ramos, J. A., Role of CB2 receptor in neuroprotective effects of cannabinoids. Mol. Cell. Endocrinol., 2008, 286, S91.

  • Makriyannis, A. and Deng, H., Cannabimimetic indole derivatives, granted 2001-06-07.

  • Makriyannis, A. and Deng, H., Cannabimimetic indole derivatives, granted 2007-07-10.

  • Murataeva, N., Mackie, K. and Straiker, A., The CB2-preferring agonist JWH-015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons. Pharmacol. Res., 2012, 66(5), 437– 442.

  • Poso, A. and Huffman, J. W., Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands. Br. J. Pharmacol., 2008, 153(2), 335–346.

  • Jacobson, M. P. et al., A hierarchical approach to all-atom protein loop prediction. Proteins: Struct., Funct. Bioinformat., 2004, 55, 351–367.

  • Jacobson, M. P., Friesner, R. A., Xiang, Z. and Honig, B., On the role of the crystal environment in determining protein side-chain conformations. J. Mol. Biol., 2002, 320, 597–608.

  • Schrödinger Release 2015-3: Prime, version 4.1, Schrödinger, LLC, New York, USA, 2015.

  • Zhu, K. et al., Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction. Prot.: Struct., Funct. Bioinformat., 2014, 82, 1646– 1655.

  • Salam, N. K., Adzhigirey, M., Sherman, W. and Pearlman, D. A., Structure-based approach to the prediction of disulfide bonds in proteins. Prot. Eng. Design Select., 2014, 27, 365–374.

  • Beard, H., Cholleti, A., Pearlman, D., Sherman, W. and Loving, K. A., Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. PLoS ONE, 2013, 8, e82849.

  • Biologics Suite 2015-3: BioLuminate, version 2.0, Schrödinger, LLC, New York, USA, 2015.

  • Protein Data Bank, repository; http://www.rcsb.org

  • Warne, T. et al., The structural basis for agonist and partial agonist action on a [bgr] 1-adrenergic receptor. Nature, 2011, 469, 241–244.

  • Hua, T. et al., Crystal structure of the human cannabinoid receptor CB1. Cell, 2016, 167, 750–762.

  • Sastry, G. M. et al., Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput-Aided Mol. Des., 2013, 27, 221–234.

  • Schrödinger Suite 2015-3 protein preparation wizard; Epik version 3.3, Schröidinger, LLC, New York, USA, 2015; Impact version 6.8, Schrödinger, LLC, New York, USA, 2015; Prime version 4.1, Schrödinger, LLC, New York, USA, 2015.

  • LigPrep, version 3.5, Schrödinger, LLC, New York, USA, 2015.

  • Farid, R., Day, T., Friesner, R. A. and Pearlstein, R. A., New insights about HERG lockade obtained from protein modeling, potential energy mapping, and docking studies. Bioor. Med. Chem., 2006, 14, 3160–3173.

  • Schrödinger Suite 2015-3 induced fit docking protocol; Glide version 6.8, Schrödinger, LLC, New York, USA, 2015; Prime version 4.1, Schrödinger, LLC, New York, USA, 2015.

  • Osman, A. G. et al., Bioactive products from singlet oxygen photooxygenation of cannabinoids. Eur. J. Med. Chem., 2018, 143, 983–996.

  • Friesner, R. A. et al., Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J. Med. Chem., 2006, 49, 6177–6196.

  • Bowers, K. J. et al., Scalable algorithms for molecular dynamics simulations on commodity clusters. In SC’06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, 2006, p 43; doi:10.1109/SC.2006.54.

  • Shivakumar, D. et al., Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J. Chem. Theory Comput., 2010, 6, 1509–1519.

  • Desmond Molecular Dynamics System, version 4.3, D. E. Shaw Research, New York, USA, 2015; Maestro-Desmond Interoperability Tools, version 4.3, Schrödinger, New York, USA, 2015.

  • Guo, Z. et al., Probing the α -helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis. Chem Biol. Drug Des., 2010, 75, 348–359.

  • Tuckerman, M. E. and Berne, B. J., Molecular dynamics algorithm for multiple timescales: systems with disparate masses. J. Chem. Phys., 1991, 94, 1465.

  • Martyna, G. J., Klein, M. L. and Tuckerman, M. E., Nose–Hoover chains: the canocial ensemble via continuous dynamics. J. Chem. Phys., 1992, 97, 2635.

  • Martyna, G. J., Tobias, D. J. and Klein, M. L., Constant pressure molecular dynamics algorithms. J. Chem. Phys., 1994, 101, 4177– 4189.

  • Cavasotto, C. N. and Phatak, S. S., Homology modeling in drug discovery: current trends and applications. Drug Discov. Today, 2009, 14, 676–683.

  • Dhopeshwarkar, A. and Mackie, K., CB2 cannabinoid receptors as a therapeutic target – what does the future hold? Mol. Pharmacol., 2014, 86(4), 430–437.

  • Malan, P. T. et al., CB2 cannabinoid receptor-mediated peripheral antinociception. Pain, 2001, 93, 239–245.

  • Aung, M. M. et al., Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding. Drug Alcohol Depend, 2000, 60(2), 133–140.

  • Frost, J. M. et al., Indol-3-ylcycloalkyl ketones: effects of N-1 substituted indole side chain variations on CB2 cannabinoid receptor activity. J. Med. Chem., 2010, 53(1), 295–315.


Abstract Views: 341

PDF Views: 153




  • Computational Insights into the Agonist Activity of Cannabinoid Receptor Type-2 Ligands Using Molecular Dynamics Simulation

Abstract Views: 341  |  PDF Views: 153

Authors

Vivek Kumar Yadav
Department of Chemistry, School of Advanced Sciences and Languages, VIT Bhopal University, Bhopal 466 114, India

Abstract


Cannabinoid (CB) receptors belong to the G protein-coupled receptor (GPCR) family and were activated by endogenous, phytogenic and synthetic modulators. The CB receptors are involved in a variety of physiological processes, including appetite, pain sensation, mood, memory, etc. The potency of ligands with receptors provides the path through which the latter show agonist, antagonist, or inverse agonist behaviour. Due to the unavailability of crystal structure of CB type-2 (CB2) receptor, we used multiple template comparative homology modelling algorithms to construct 3D models for the same. We performed docking and molecular dynamics simulation study of four synthetic drugs in both cannabinoid type-1 (CB1) and CB2 receptors. These ligands show agonist activity with the CB2 receptor and activates it completely. The results are compared with the CB1 receptor. Molecular properties of the ligands, including molecular, polar and solvent-accessible surface areas, and intramolecular hydrogen bonds were evaluated using molecular dynamics simulations. Our finding demonstrates that the ligand AM-1221 shows the highest binding affinity (–12.73 k cal/mol), whereas UR-144 shows the lowest (–9.83 k cal/mol) towards the CB2 receptor. These findings should stimulate the design of ligands with distinct pharmacological properties associated with the CB2 receptor.

Keywords


Agonist Activity, Cannabinoid Receptors, Induced Fit Docking, Ligands, Molecular Dynamics Simulations.

References





DOI: https://doi.org/10.18520/cs%2Fv122%2Fi2%2F167-177