Journal of Integrative Natural Science (통합자연과학논문집)

The Basic Science Institute Chosun University (조선대학교 기초과학연구원)
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In-silico Modeling of Chemokine Receptor CCR2 And CCR5 to Assist the Design of Effective and Selective Antagonists

  • Kothandan, Gugan (Department of Bio-New Drug Development, College of Medicine, Chosun University) ;
  • Cho, Seung Joo (Department of Cellular.Molecular Medicine and Research Center for Resistant Cells, College of Medicine, Chosun University)
  • Received : 2011.10.23
  • Accepted : 2012.03.27
  • Published : 2012.03.30
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Abstract

Chemokine receptor antagonists have potential applications in field of drug discovery. Although the chemokine receptors are G-protein-coupled receptors, their cognate ligands are small proteins (8 to 12 kDa), and so inhibiting the ligand/receptor interaction has been challenging. The application of structure-based in-silico methods to drug discovery is still considered a major challenge, especially when the x-ray structure of the target protein is unknown. Such is the case with human CCR2 and CCR5, the most important members of the chemokine receptor family and also a potential drug target. Herein, we review the success stories of combined receptor modeling/mutagenesis approach to probe the allosteric nature of chemokine receptor binding by small molecule antagonists for CCR2 and CCR5 using Rhodopsin as template. We also urged the importance of recently available ${\beta}2$-andrenergic receptor as an alternate template to guide mutagenesis. The results demonstrate the usefulness and robustness of in-silico 3D models. These models could also be useful for the design of novel and potent CCR2 and CCR5 antagonists using structure based drug design.

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References

  1. F. Sallusto and M. Baggiolini, "Chemokines and leukocyte traffic", Tat. Immunol., Vol. 9, pp. 949-952, 2008.
  2. A. Viola and A. D. Luster, "Chemokines and their receptors: Drug targets in immunity and inflammation", Annu. Rev. Pharmacol. Toxicol., Vol. 48, pp. 171-197, 2008. https://doi.org/10.1146/annurev.pharmtox.48.121806.154841
  3. S. J Allen, S. E. Crown and T. M. Handel, "Chemokine: Receptor structure, interactions, and antagonism", Annu. Rev. Immunol., Vol. 25, pp. 787-820, 2007. https://doi.org/10.1146/annurev.immunol.24.021605.090529
  4. I. F. Charo and R. M. Ransohoff, "The Many Roles of Chemokines and Chemokine Receptors in Inflammation", N. Engl. J. Med., Vol. 354, pp. 610-621, 2006. https://doi.org/10.1056/NEJMra052723
  5. J. G. Kettle, A. W. Faull, A. J. Barker, D. Huw Davies and M. A. Stone, "N-Benzylindole-2-carboxylic acids: potent functional antagonists of the CCR2b chemokine receptor", Bioorg. Med. Chem. Lett., Vol. 14, pp. 405-408, 2004. https://doi.org/10.1016/j.bmcl.2003.10.049
  6. C. Zhou, L. Guo, W. H. Parsons, S. G. Mills, M. MacCoss, P. P. Vicario, H. Zweerink, M. A. Cascieri, M. S. Springerb and L. Yanga, "$\alpha$-Ami-nothiazole-$\gamma$-aminobutanoic amides as potent, small molecule CCR2 receptor antagonists", Bioorg. Med. Chem. Lett., Vol. 17, pp. 309-314, 2007. https://doi.org/10.1016/j.bmcl.2006.10.059
  7. M. Imai, T. Shiota, K. Kataoka, C. M. Tarby, W. J. Moree, T. Tsutsumi, M. Sudo, M. M. Ramirez- Weinhouse, D. Comer, C. M. Sun, S. Yamagami, H. Tanaka, T. Morita, T. Hada, J. Greene, D. Barnum, J. Saunders, P. L. Myers, Y. Katoa and N. Endoa, "Small molecule inhibitors of the CCR2b receptor. Part 1: Discovery and optimization of homopiperazine derivatives", Bioorg. Med. Chem. Lett., Vol. 14, pp. 5407-5411, 2004. https://doi.org/10.1016/j.bmcl.2004.08.008
  8. W. J. Moree, K. I. Kataoka, M. M. Ramirez-Weinhouse, T. Shiota, M. Imai, M. Sudo, T. Tsutsumi, N. Endo, Y. Muroga, T. Hada, H. Tanaka, T. Morita, J. Greene, D. Barnum, J. Saunders, Y. Kato, P. L. Myers and C. M. Tarby, "Small molecule antagonists of the CCR2b receptor. Part 2: Discovery process and initial structure-activity relationships of diamine derivatives", Bioorg. Med. Chem. Lett., Vol. 14, pp. 5413-5416, 2004. https://doi.org/10.1016/j.bmcl.2004.08.009
  9. S. P. Weisberg, D. Hunter, R. Huber, J. Lemieux, S. Slaymaker, K. Vaddi, I. Charo, R. L. Leibel, A. and W. Ferrante Jr, "CCR2 modulates inflammatory and metabolic effects of high-fat feeding", J. Clin. Investig., Vol. 116, pp. 115-124, 2006. https://doi.org/10.1172/JCI24335
  10. C. D. Strader, T. M. Fong, M. R. Tota, D. Underwood and R. A. F. Dixon, "Structure and function of G protein-coupled receptors", Annu. Rev. Biochem., Vol. 63, pp 101-132, 1992.
  11. F. Cocchi, A. L. DeVico, A. Garzino-Demo, S. K. Arya, R. C. Gallo and P. Lusso, "Identification of RANTES, MIP-1$\alpha$ and MIP-$1\beta$ as the major HIVsuppressive factors produced by CD8+ T cells", Science., Vol. 270, pp 1811-1815, 1995. https://doi.org/10.1126/science.270.5243.1811
  12. R. Liu, W.A. Paxton, S. Choe, D. Ceradini, S. R. Martin, R. Horuk, M. E. MacDonald, H. Stuhlmann, R. A. Koup and N. R. Landau, "Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection", Cell., Vol. 86, pp. 367-378, 1996. https://doi.org/10.1016/S0092-8674(00)80110-5
  13. M. Samson, F. Libert, B. J. Doranz, J. Rucker, C. Liesnard, C. M. Farber, S. Saragosti, C. Lapoumeroulie, J. Cognaux, C. Forceille, G. Muyldermans, C. Verhofstede, G. Burtonboy, M. Georges and T. Imai, "Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene", Nature., Vol. 382, pp. 722-725, 1996. https://doi.org/10.1038/382722a0
  14. T. Dragic, A. Trkola, D. A. D. Thompson, E. G. Cormier, F. A. Kajumo, E. Maxwell, S. W. Lin, W. Ying, S. O. Smith, T. P. Sakmar and J. P. Moore, "A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5", Proc. Natl. Acad. Sci. USA., Vol. 97, pp. 5639-5644, 2000. https://doi.org/10.1073/pnas.090576697
  15. M. Baba, O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, K. Okonogi, Y. Ogawa, K. Meguro and M. Fujino, "A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity", Proc. Natl. Acad. Sci. USA., Vol. 96, pp. 5698-5703, 1999. https://doi.org/10.1073/pnas.96.10.5698
  16. J. M. Strizki, S. Xu, N. E. Wagner, L. Wojcik, J. Liu, Y. Hou, M. Endres, A. Palani, S. Shapiro, J. W. Clader, W. J. Greenlee, J. R. Tagat, S. McCombie, K. Cox and A. B. Fawzi, "SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo", Proc. Natl. Acad. Sci. USA., Vol. 98, pp. 12718-12723, 2001. https://doi.org/10.1073/pnas.221375398
  17. P. Dorr, M. Westby, S. Dobbs, P. Griffin, B. Irvine, M. Macartney, J. Mori, G. Rickett, C. Smith-Burchnell, C. Napier, R. Webster, D. Armour, D. Price, B. Stammen, and A. Wood, "Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity", Antimicrob. Agents. Chemother., Vol. 49, pp. 4721-4732, 2006.
  18. K. Maeda, H. Nakata, Y. Koh, T. Miyakawa, H. Ogata, Y. Takaoka, S. Shibayama, K. Sagawa, D. Fukushima, J. Moravek, Y. Koyanagi amd H. Mitsuya, "Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro", J. Virol., Vol.78, pp. 8654-8662, 2004. https://doi.org/10.1128/JVI.78.16.8654-8662.2004
  19. W. G. Nichols, H. M. Steel, T. Bonny, K. Adkison, L. Curtis, J. Millard, K. Kabeya and N. Clumeck, "Hepatotoxicity observed in clinical trials of aplaviroc (GW873140)", Antimicrob. Agents. Chemother., Vol. 52, pp. 858-865, 2008. https://doi.org/10.1128/AAC.00821-07
  20. J. M. Strizki, C. Tremblay, S. Xu, L. Wojcik, N. Wagner, W. Gonsiorek, R. W. Hipkin, C. C.C Chou, C. Pugliese-Sivo, Y. Xiao, J. R. Tagat, K. Cox, T. Priestley, S. Sorota and W. Huang, "Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1", Antimicrob. Agents. Chemother., Vol. 49, pp. 4911-4919, 2005 . https://doi.org/10.1128/AAC.49.12.4911-4919.2005
  21. J. R. Tagat, S. W. McCombie, D. Nazareno, M. A. Labroli, Y. Xiao, R. W. Steensma, J. M. Strizki, B. M. Baroudy, K. Cox, J. Lachowicz, G. Varty and R. Watkins, "Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4, 6-dimethyl-5-pyrimidinyl) carbonyl]-4-[4-[2-methoxy-1 (R)-4- (trifluoromethyl) phenyl] ethyl-3 (S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist", J. Med. Chem., Vol. 47, pp. 2405-2408, 2004. https://doi.org/10.1021/jm0304515
  22. X. F. Shi, S. Liu, J. Xiangyu, Y. Zhang, J. Huang, S. Liu and C. Q. Liu, "Structural analysis of human CCR2b and primate CCR2b by molecular modeling and molecular dynamics simulation", J. Mol. Model., Vol. 8, pp. 217-222, 2002. https://doi.org/10.1007/s00894-002-0089-6
  23. T. Mirzaddegan, F. Diehl, B. Ebi, S. Bhakta, I. Polsky, D. McCarley, M. Mulkins, G. S. Weatherhead, J. M. Lapierre, J. Dankwardt, D. Morgans, J. R, William and K. Jarnagin, "Identification of the Binding site for a novel class of CCR2b Chemokine receptor antagonists", J. Biol. Chem., Vol. 275, pp. 25562-25571, 2000. https://doi.org/10.1074/jbc.M000692200
  24. T. A. Berkhout, F. E. Blaney, A. M. Bridges, D. G. Cooper, I. T. Forbes, A. D. Gribble, P. H. E. Groot, A. Hardy, R. J. Ife, R. Kaur,K. E. Moores, H. Shillito, J. Willets and J. Witherington, "CCR2: Characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach", J. Med. Chem., Vol. 46, pp. 4070-4086, 2003. https://doi.org/10.1021/jm030862l
  25. A. Fano, D. W. Ritchie, and A. Carrieri, "Modeling the Structural Basis of Human CCR5 Chemokine Receptor Function: From Homology Model Building and Molecular Dynamics Validation to Agonist and Antagonist Docking", J. Chem. Inf. Model., Vol. 46, pp. 1223-1235, 2006. https://doi.org/10.1021/ci050490k
  26. R. Kondru, J. Zhang, C. Ji, T. Mirzadegan, D. Rotstein, S. Sankuratri, and M. Dioszegi, "Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists", Mol. Pharmacol., Vol. 73, pp. 789-800, 2008.
  27. K. Maeda, D. Das, H. Ogata-Aoki, H. Nakata, T. Miyakawa, Y. Tojo, R. Norman, Y. Takaoka, J. Ding, G. F. Arnold, Eddy Arnold, and Hiroaki Mitsuya, "Structural and Molecular Interactions of CCR5 Inhibitors with CCR5", J. Biol. Chem., Vol. 281, pp. 12688-12698, 2006. https://doi.org/10.1074/jbc.M512688200
  28. L. A. Castonguay, Y. Weng, W. Adolfsen, J. Di Salvo, R. Kilburn, C. G. Caldwell, B. L. Daugherty, P. E. Finke, J. J. Hale, C. L. Lynch, S. G. Mills, M. MacCoss, M. S. Springer, and Julie A. DeMartino, "Binding of 2-Aryl-4-(piperidin-1-yl)butanamines and 1,3,4-Trisubstituted Pyrrolidines to Human CCR5: A Molecular Modeling-Guided Mutagenesis Study of the Binding Pocket", Biochem., Vol. 42, pp. 1544-1550, 2003. https://doi.org/10.1021/bi026639s