Citation: ZENG Ling-Xiao, LI Xin-Ran, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren. Comparison of the Selectivity of Human Adenosine Receptor Anta nists Based on Structure and Pharmacophore Features[J]. Acta Physico-Chimica Sinica, ;2015, 31(8): 1584-1596. doi: 10.3866/PKU.WHXB201505253
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Adenosine receptors (ARs) are crucial therapeutic targets, and selective adenosine receptor anta nists are promising for numerous therapeutic applications. In this study, three dimensional models of human adenosine A1, A2B, and A3 receptors (A1AR, A2BAR, A3AR, respectively) were generated by homology modeling. In addition, pharmacophore models of the anta nists of four human adenosine receptor subtypes were developed using the LigandScout 3.12 program. Furthermore, Induced Fit Docking module of Schrödinger program was implemented to investigate receptor-ligand interactions. The results show that because of the subfamily-wide conservation of the core pocket residues, the ligand binding pockets of the three raw AR homology models are extremely similar, which poses challenges for subtype selective ligand recognition. However, the pharmacophore models of the four AR subtypes differ in pharmacophore features and spatial configuration, which are also consistent with previous site-directed mutagenesis studies. This indicates that binding site optimization is a crucial step in model generation, and the distributions for a set of pharmacophore features in ligand-based pharmacophore, including hydrogen bond acceptors, hydrogen bond donors, hydrophobic centroids, and aromatic rings, can reflect the position and direction characterization of hydrogen bonds and hydrophobic cavities, which aid identification and characterization of binding sites. This study may provide a significant theoretical foundation for further raw model optimization in homology modeling and discovery of novel selective human adenosine receptor anta nists.
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Keywords:
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Pharmacophore
, - Human adenosine receptor,
- Anta nist,
- Selectivity
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[1]
(1) Krishnan, A.; Almen, M. S.; Fredriksson, R.; Schioth, H. B. PLoS One 2012, 7 (1), e29817.
-
[2]
(2) Lappano, R.; Maggiolini, M. Nat. Rev. Drug Discov. 2011, 10 (1), 47. doi: 10.1038/nrd3320
-
[3]
(3) Liang, F.; Yue, J.; Wang, J.; Zhang, L.; Fan, R.; Zhang, H.; Zhang, Q. Med. Oncol. 2015, 32 (3), 49. doi: 10.1007/s12032-015-0486-1
-
[4]
(4) Overington, J. P.; Al-Lazikani, B.; Hopkins, A. L. Nat. Rev. Drug Discov. 2006, 5 (12), 993. doi: 10.1038/nrd2199
-
[5]
(5) Chen, J. F.; Eltzschig, H. K.; Fredholm, B. B. Nat. Rev. Drug Discov. 2013, 12 (4), 265. doi: 10.1038/nrd3955
-
[6]
(6) Ke, Y. R.; Jin, H. W.; Liu, Z. M.; Zhang, L. R. Acta Phys. -Chim. Sin. 2010, 26 (10), 2833. [柯艳蓉, 金宏威, 刘振明, 张亮仁. 物理化学学报, 2010, 26 (10), 2833.] doi: 10.3866/PKU.WHXB20100916
-
[7]
(7) Robeva, A. S.; Woodard, R. L.; Jin, X.; Gao, Z.; Bhattacharya, S.; Taylor, H. E.; Rosin, D. L.; Linden, J. Drug Develop. Res. 1996, 39 (3-4), 243.
-
[8]
(8) Fredholm, B. B.; AP, I. J.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Pharmacol. Rev. 2001, 53 (4), 527.
-
[9]
(9) Jacobson, K. A.; Gao, Z. G. Nat. Rev. Drug Discov. 2006, 5 (3), 247. doi: 10.1038/nrd1983
-
[10]
(10) Sliwoski, G.; Kothiwale, S.; Meiler, J.; Lowe, E. W., Jr. Pharmacol. Rev. 2014, 66 (1), 334.
-
[11]
(11) Congreve, M.; Langmead, C. J.; Mason, J. S.; Marshall, F. H. J. Med. Chem. 2011, 54 (13), 4283. doi: 10.1021/jm200371q
-
[12]
(12) Costanzi, S. Methods Mol. Biol. 2012, 857, 259.
-
[13]
(13) Katritch, V.; Kufareva, I.; Abagyan, R. Neuropharmacology 2011, 60 (1), 108. doi: 10.1016/j.neuropharm.2010.07.009
-
[14]
(14) Güner, O. F. Pharmacophore Perception, Development, and Use in Drug Design; International University Line: San Die , 2000; Vol. 2.
-
[15]
(15) Khedkar, S. A.; Malde, A. K.; Coutinho, E. C.; Srivastava, S. Med. Chem. 2007, 3 (2), 187. doi: 10.2174/157340607780059521
-
[16]
(16) Liu, W.; Chun, E.; Thompson, A. A.; Chubukov, P.; Xu, F.; Katritch, V.; Han, G. W.; Roth, C. B.; Heitman, L. H.; Ijzerman, A P.; Cherezov, V.; Stevens, R. C. Science 2012, 337 (6091), 232. doi: 10.1126/science.1219218
-
[17]
(17) Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M. C.; Estreicher, A.; Gasteiger, E.; Martin, M. J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.Nucleic. Acids Res. 2003, 31 (1), 365. doi: 10.1093/nar/gkg095
-
[18]
(18) Discovery Studio 2.5, Release 2.5; Accelrys Software Inc.: San Die , 2009.
-
[19]
(19) Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. J. Appl. Cystallogr. 1993, 26, 283. doi: 10.1107/S0021889892009944
-
[20]
(20) Lin, K. J.; Zhu, D. J.; Leng, Y. G.; You, Q. D. Acta Phys. -Chim. Sin. 2012, 28 (7), 1783. [林克江, 朱冬吉, 冷勇敢, 尤启冬. 物理化学学报, 2012, 28 (7), 1783.] doi: 10.3866/PKU.WHXB201204192
-
[21]
(21) Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. Nucleic. Acids Res. 2012, 40 (Database issue), D1100.
-
[22]
(22) Xia, J.; Jin, H.; Liu, Z.; Zhang, L.; Wang, X. S. J. Chem. Inf. Model. 2014, 54 (5), 1433. doi: 10.1021/ci500062f
-
[23]
(23) Xia, J.; Tilahun, E. L.; Reid, T. E.; Zhang, L.; Wang, X. S. Methods 2015, 71, 146. doi: 10.1016/j.ymeth.2014.11.015
-
[24]
(24) Qiao, K.; Zeng, L. X.; Jin, H. W.; Liu, Z. M.; Zhang, L. R. Acta Phys. -Chim. Sin. 2012, 28 (6), 1509. [乔康, 曾凌晓, 金宏威, 刘振明, 张亮仁. 物理化学学报, 2012, 28(6), 1509.] doi: 10.3866/PKU. WHXB201203272
-
[25]
(25) Wolber, G.; Langer, T. J. Chem. Inf. Model. 2005, 45 (1), 160. doi: 10.1021/ci049885e
-
[26]
(26) Schrödinger Suite 2013; Schrödinger, LLC: New York, 2013.
-
[27]
(27) Ballesteros, J. A.; Weinstein, H. Methods Neurosci. 1995, 25, 366.
-
[28]
(28) Kiesman, W. F.; Zhao, J.; Conlon, P. R.; Dowling, J. E.; Petter, R. C.; Lutterodt, F.; Jin, X.; Smits, G.; Fure, M.; Jayaraj, A.; Kim, J.; Sullivan, G.; Linden, J. J. Med. Chem. 2006, 49 (24), 7119.
-
[29]
(29) Giovannoni, M. P.; Vergelli, C.; Cilibrizzi, A.; Crocetti, L.; Biancalani, C.; Graziano, A.; Dal Piaz, V.; Loza, M. I.; Cadavid, M. I.; Diaz, J. L.; Gavalda, A. Bioorg. Med. Chem. 2010, 18 (22), 7890. doi: 10.1016/j.bmc.2010.09.043
-
[30]
(30) Chang, L. C.; Kuenzel, J. V.; Mulder-Krieger, T.; Westerhout, J.; Spangenberg, T.; Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2007, 50 (4), 828. doi: 10.1021/jm0607956
-
[31]
(31) Scheiff, A. B.; Yerande, S. G.; El-Tayeb, A.; Li, W.; Inamdar, G. S.; Vasu, K. K.; Sudarsanam, V.; Muller, C. E. Bioorg. Med. Chem. 2010, 18 (6), 2195. doi: 10.1016/j.bmc. 2010.01.072
-
[32]
(32) Novellino, E.; Cosimelli, B.; Ehlardo, M.; Greco, G.; Iadanza, M.; Lavecchia, A.; Rimoli, M. G.; Sala, A.; Da Settimo, A.; Primofiore, G.; Da Settimo, F.; Taliani, S.; La Motta, C.; Klotz, K. N.; Tuscano, D.; Trincavelli, M. L.; Martini, C. J. Med. Chem. 2005, 48 (26), 8253.
-
[33]
(33) Mishra, C. B.; Barodia, S. K.; Prakash, A.; Kumar, J. B. S.; Luthra, P. M. Bioorg. Med. Chem. 2010, 18 (7), 2491. doi: 10.1016/j.bmc.2010.02.048
-
[34]
(34) Moorjani, M.; Zhang, X.; Chen, Y.; Lin, E.; Rueter, J. K.; Gross, R. S.; Lanier, M. C.; Tellew, J. E.; Williams, J. P.; Lechner, S. M.; Malany, S.; Santos, M.; Ekhlassi, P.; Castro-Palomino, J. C.; Crespo, M. I.; Prat, M.; Gual, S.; Diaz, J. L.; Saunders, J.; Slee, D. H. Bioorg. Med. Chem. Lett. 2008, 18 (4), 1269. doi: 10.1016/j.bmcl.2008.01.036
-
[35]
(35) Gillespie, R. J.; Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Gaur, S.; Jordan, A. M.; Knight, A. R.; Lerpiniere, J.; Misra, A.; Pratt, R. M.; Roffey, J.; Stratton, G. C.; Upton, R.; Weiss, S. M.; Williamson, D. S. Bioorg. Med. Chem. Lett. 2008, 18 (9), 2924. doi: 10.1016/j.bmcl.2008.03.072
-
[36]
(36) Gillespie, R. J.; Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Gaur, S.; Giles, P. R.; Jordan, A. M.; Knight, A. R.; Lawrence, A.; Lerpiniere, J.; Misra, A.; Pratt, R. M.; Todd, R. S.; Upton, R.; Weiss, S. M.; Williamson, D. S. Bioorg. Med. Chem. Lett. 2008, 18 (9), 2920. doi: 10.1016/j.bmcl.2008.03.076
-
[37]
(37) Gillespie, R. J.; Bamford, S. J.; Clay, A.; Gaur, S.; Haymes, T.; Jackson, P. S.; Jordan, A. M.; Klenke, B.; Leonardi, S.; Liu, J.; Mansell, H. L.; Ng, S.; Saadi, M.; Simmonite, H.; Stratton, G. C.; Todd, R. S.; Williamson, D. S.; Yule, I. A. Bioorg. Med. Chem. 2009, 17 (18), 6590. doi: 10.1016/j.bmc.2009.07.078
-
[38]
(38) Silverman, L. S.; Caldwell, J. P.; Greenlee, W. J.; Kisel f, E.; Matasi, J. J.; Tulshian, D. B.; Arik, L.; Foster, C.; Bertorelli, R.; Monopoli, A.; Ongini, E. Bioorg. Med. Chem. Lett. 2007, 17 (6), 1659. doi: 10.1016/j.bmcl.2006.12.104
-
[39]
(39) Firooznia, F.; Cheung, A. W.; Brinkman, J.; Grimsby, J.; Gubler, M. L.; Hamid, R.; Marcopulos, N.; Ramsey, G.; Tan, J.; Wen, Y.; Sarabu, R. Bioorg. Med. Chem. Lett. 2011, 21 (7), 1933. doi: 10.1016/j.bmcl.2011.02.053
-
[40]
(40) Cheung, A. W.; Brinkman, J.; Firooznia, F.; Flohr, A.; Grimsby, J.; Gubler, M. L.; Guertin, K.; Hamid, R.; Marcopulos, N.; Norcross, R. D.; Qi, L.; Ramsey, G.; Tan, J.; Wen, Y.; Sarabu, R. Bioorg. Med. Chem. Lett. 2010, 20 (14), 4140. doi: 10.1016/j.bmcl.2010.05.056
-
[41]
(41) Kalla, R. V.; Elzein, E.; Perry, T.; Li, X.; Palle, V.; Varkhedkar, V.; Gimbel, A.; Maa, T.; Zeng, D.; Zablocki, J. J. Med. Chem. 2006, 49 (12), 3682. doi: 10.1021/jm051268+
-
[42]
(42) Kim, Y. C.; Ji, X.; Melman, N.; Linden, J.; Jacobson, K. A. J. Med. Chem. 2000, 43 (6), 1165. doi: 10.1021/jm990421v
-
[43]
(43) Stefanachi, A.; Nicolotti, O.; Leonetti, F.; Cellamare, S.; Campagna, F.; Loza, M. I.; Brea, J. M.; Mazza, F.; Gavuzzo, E.; Carotti, A. Bioorg. Med. Chem. 2008, 16 (22), 9780. doi: 10.1016/j.bmc.2008.09.067
-
[44]
(44) Da Settimo, F.; Primofiore, G.; Taliani, S.; Marini, A. M.; La Motta, C.; Simorini, F.; Salerno, S.; Sergianni, V.; Tuccinardi, T.; Martinelli, A.; Cosimelli, B.; Greco, G.; Novellino, E.; Ciampi, O.; Trincavelli, M. L.; Martini, C. J. Med. Chem. 2007, 50 (23), 5676. doi: 10.1021/jm0708376
-
[45]
(45) Prie , E. M.; Kuenzel, J. V.; Ijzerman, A. P.; Camarasa, M. J.; Perez-Perez, M. J. J. Med. Chem. 2002, 45 (16), 3337. doi: 10.1021/jm0208469
-
[46]
(46) Melman, A.; Wang, B.; Joshi, B. V.; Gao, Z. G.; Castro, S.; Heller, C. L.; Kim, S. K.; Jeong, L. S.; Jacobson, K. A. Bioorg. Med. Chem. 2008, 16 (18), 8546. doi: 10.1016/j.bmc.2008.08.007
-
[47]
(47) Baraldi, P. G.; Cacciari, B.; Moro, S.; Spalluto, G.; Pastorin, G.; Da Ros, T.; Klotz, K. N.; Varani, K.; Gessi, S.; Borea, P. A. J. Med. Chem. 2002, 45 (4), 770. doi: 10.1021/jm0109614
-
[48]
(48) Colotta, V.; Catarzi, D.; Varano, F.; Capelli, F.; Lenzi, O.; Filacchioni, G.; Martini, C.; Trincavelli, L.; Ciampi, O.; Pugliese, A. M.; Pedata, F.; Schiesaro, A.; Morizzo, E.; Moro, S. J. Med. Chem. 2007, 50 (17), 4061. doi: 10.1021/jm070123v
-
[49]
(49) Jaakola, V. P.; Griffith, M. T.; Hanson, M. A.; Cherezov, V.; Chien, E. Y.; Lane, J. R.; Ijzerman, A. P.; Stevens, R. C. Science 2008, 322 (5905), 1211. doi: 10.1126/science.1164772
-
[50]
(50) Olah, M. E.; Ren, H.; Ostrowski, J.; Jacobson, K. A.; Stiles, G. L. J. Biol. Chem. 1992, 267 (15), 10764.
-
[51]
(51) Rivkees, S. A.; Barbhaiya, H.; Ijzerman, A. P. J. Biol. Chem. 1999, 274 (6), 3617. doi: 10.1074/jbc.274.6.3617
-
[52]
(52) Jaakola, V. P.; Lane, J. R.; Lin, J. Y.; Katritch, V.; Ijzerman, A. P.; Stevens, R. C. J. Biol. Chem. 2010, 285 (17), 13032. doi: 10.1074/jbc.M109.096974
-
[53]
(53) Cheng, F.; Xu, Z.; Liu, G.; Tang, Y. Eur. J. Med. Chem. 2010, 45 (8), 3459. doi: 10.1016/j.ejmech.2010.04.039
-
[54]
(54) Thimm, D.; Schiedel, A. C.; Sherbiny, F. F.; Hinz, S.; Hochheiser, K.; Bertarelli, D. C.; Maass, A.; Muller, C. E. Biochemistry-US 2013, 52 (4), 726. doi: 10.1021/bi3012065
-
[55]
(55) Ivanov, A. A.; Baskin, II.; Palyulin, V. A.; Piccagli, L.; Baraldi, P. G.; Zefirov, N. S. J. Med. Chem. 2005, 48 (22), 6813. doi: 10.1021/jm049418o
-
[56]
(56) Gao, Z. G.; Kim, S. K.; Biadatti, T.; Chen, W.; Lee, K.; Barak, D.; Kim, S. G.; Johnson, C. R.; Jacobson, K. A. J. Med. Chem. 2002, 45 (20), 4471. doi: 10.1021/jm020211+
-
[57]
(57) Muller, C. E.; Jacobson, K. A. BBA-Biomembranes 2011, 1808 (5), 1290. doi: 10.1016/j.bbamem.2010.12.017
-
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