Discovery and validation of potential drug targets based on the phylogenetic evolution of GPCRs


Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. G-protein coupled recaptors (GPCRs) are among the most important drug targets for the pharmaceutical industry. The present work seeks to provide an in silico model of known GPCR protein fishing technologies in order to rapidly fish out potential drug targets on the basis of amino acid sequences and seven transmembrane regions (TMs) of GPCRs. Some scoring matrices were trained on 22 groups of GPCRs in the GPCRDB database. These models were employed to predict the GPCR proteins in two groups of test sets. On average, the mean correct rate of each TM of 38 GPCRs from two test sets (ST23 and ST24) was found 62% and 57.5%, respectively, using training set 18 (SLD18); the mean hit rate of each TM of 38 GPCRs from ST23 and ST24 was found 68.1% and 64.7%, respectively. Based on the scoring matrices of PreMod, the mean correct rate of each TM of GPCRs from ST23 and ST24 was found 62% and 62.04%, respectively; the mean hit rate of each TM of GPCRs from ST23 and ST24 was found 67.7% and 68.0%, respecttively. The means of GPCRs in ST23 based on SLD18 is close to those based on PreMod; whereas the means of GPCRs in ST24 based on SLD18 is less than those based on PreMod. Moreover, the accuracy (“2”) and validity (“2 + 1”) rates of prediction all seven TMs of 38 GPCRs by the scoring matrices of PreMod are more than those by SLD18, SLA14 and SLA3; whereas the hit rates (94.74% and 97.37%) by PreMod are less than those of SLA3 but bigger than those of SLD18 and SLA14, respectively. This is the reason that we choose PreMod to predict some potential drug targets. 22 GPCR proteins in the sense chain of chromosome 19 constructing validation set were predicted and validated by PreMod whose hit rate is up to 90.91%. Further evaluation is under investigation.

Share and Cite:

Yang, J. , Li, S. , Zhu, T. , Wang, X. and Zhang, Z. (2012) Discovery and validation of potential drug targets based on the phylogenetic evolution of GPCRs. Natural Science, 4, 1109-1152. doi: 10.4236/ns.2012.412A139.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] [1] Hopkins, A.L. and Groom, C.R. (2002) The druggable genome. Nature Reviews Drug Discovery, 1, 727-730. doi:/10.1038/nrd892
[2] Neves, S.R., Ram, P.T. and Iyengar, R. (2002) G protein pathways. Science, 296, 1636-1639. doi:/10.1126/science.1071550
[3] Hynes, R.O. (2002) Integrins: Bidirectional, allosteric signaling machines. Cell, 110, 673-687. doi:/10.1016/S0092-8674(02)00971-6
[4] Tilley, D.G. (2011) G protein-dependent and G proteinindependent signaling pathways and their impact on cardiac function. Circulation Research, 109, 217-230. doi:/10.1161/CIRCRESAHA.110.231225
[5] Shen, B., Delaney, M.K. and Du, X. (2012) Inside-out, outside-in, and inside-outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Current Opinion in Cell Biology, 24, 600-606. doi:/10.1016/
[6] Jaffe, A.B. and Hall, A. (2005) Rho GTPases: Biochemistry and biology. Annual Review of Cell and Developmental Biology, 21, 247-269. doi:/10.1146/annurev.cellbio.21.020604.150721
[7] Bockaert, J. and Pin, J.P. (1999) Molecular tinkering of G protein-coupled receptors:an evolutionary success. The EMBO Journal, 18, 1723-1729. doi:/10.1093/emboj/18.7.1723
[8] Vassilatis. D.K., Hohmann, J.G., Zeng, H., Li, F., Ranchalis, J.E., Mortrud, M.T., Brown, A., Rodriguez, S.S., Weller, J.R., Wright, A.C., Bergmann, J.E. and Gaitanaris, G.A. (2003) The G protein-coupled receptor repertoires of human and mouse. Proceedings of the National Academy of Sciences of the United States of America, 100, 4903-4908. doi:/10.1073/pnas.0230374100
[9] Foord, S.M., Bonner, T.I., Neubig, R.R., Rosser, E.M., Pin, J.P., Davenport, A.P., Spedding, M. and Harmar, A.J. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacological Reviews, 57, 279-288. doi:/10.1124/pr.57.2.5
[10] Horn, F., Weare, J., Beukers, M.W., H?rsch, S., Bairoch, A., Chen, W., Edvardsen, O., Campagne, F. and Vriend, G. (1998) GPCRDB: An information system for G protein-coupled receptors. Nucleic Acids Research, 26, 275- 279.doi:/10.1093/nar/26.1.275
[11] Attwood, T.K. and Findlay, J.B. (1994). Fingerprinting G-protein-coupled receptors. Protein Engineering, 7, 195-203. doi:/10.1093/protein/7.2.195
[12] Harmar, A.J. (2001). Family-B G-protein-coupled receptors. Genome Biology, 2, 3013.1-3013.10. doi:/10.1186/gb-2001-2-12-reviews3013
[13] Br?uner-Osborne, H., Wellendorph, P. and Jensen, A.A. (2007) Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Current Drug Targets, 8, 169-184. doi:/10.2174/138945007779315614
[14] Herskowitz, I. and Marsh, L. (1988). STE2 protein of Saccharomyces kluyveri is a member of the rhodopsin/ beta-adrenergic receptor family and is responsible for recognition of the peptide ligand alpha factor. Proceedings of the National Academy of Sciences of the United States of America, 85, 3855-3859. doi:/10.1073/pnas.85.11.3855
[15] Devreotes, P.N., Kimmel, A.R., Johnson, R.L., Klein, P.S., Sun, T.J. and Saxe III, C.L. (1988). A chemoattractant receptor controls development in Dictyostelium discoideum. Science, 241, 1467-1472. doi:/10.1126/science.3047871
[16] Malbon, C.C. (2004). Frizzleds: New members of the superfamily of G-protein-coupled receptors. Frontiers in Bioscience, 9, 1048-1058. doi:/10.2741/1308
[17] Taipale, J., Chen, J.K., Cooper, M.K., Wang, B., Mann, R.K., Milenkovic, L., Scott, M.P. and Beachy, P.A. (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature, 406, 1005-1009. doi:/10.1038/35023008
[18] Buck, L. and Axel, R. (1991) A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell, 65, 175-187. doi:/10.1016/0092-8674(91)90418-X
[19] Mombaerts, P. (1999) Seven-transmembrane proteins as odorant and chemosensory receptors. Science, 286, 707- 711. doi:/10.1126/science.286.5440.707
[20] Firestein, S. (2000) The good taste of genomics. Nature 404, 552-553. doi:/10.1038/35007167
[21] Howard, A.D., McAllister, G., Feighner, S.D., Liu, Q., Nargund, R.P., Van der Ploeg, L.H. and Patchett, A.A. (2001) Orphan G-protein-coupled receptors and natural ligand discovery. Trends in Pharmacological Sciences, 22, 132-140. doi:/10.1016/S0165-6147(00)01636-9
[22] Lee, D.K., George, S.R., Evans, J.F., Lynch, K.R. and O’ Dowd, B.F. (2001) Orphan G protein-coupled receptors in the CNS. Current Opinion in Pharmacology, 1, 31-39. doi:/10.1016/S1471-4892(01)00003-0
[23] Filmore, D. (2004) It’s a GPCR world. Modern Drug Discovery, 11, 24-28.
[24] Wise, A., Gearing, K. and Rees, S. (2002) Target validation of G-protein coupled receptors. Drug Discovery Today, 7, 235-246. doi:/10.1016/S1359-6446(01)02131-6
[25] Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G., Smith, H.O., Yandell, M., Evans, C.A., Holt, R.A., Gocayne, J.D., Amanatides, P., Ballew, R.M., Huson, D.H., Wortman, J.R., Zhang, Q., Kodira, C.D., Zheng, X.H., Chen, L., Skupski, M., Subramanian, G., Thomas, P.D., Zhang, J., Gabor Miklos, G.L., Nelson, C., Broder, S., Clark, A.G., Nadeau, J., McKusick, V.A., Zinder, N., Levine, A.J., Roberts, R.J., Simon, M., Slayman, C., Hunkapiller, M., Bolanos, R., Delcher, A., Dew, I., Fasulo, D., Flanigan, M., Florea, L., Halpern, A., Hannenhalli, S., Kravitz, S., Levy, S., Mobarry, C., Reinert, K., Remington, K., Abu-Threideh, J., Beasley, E., Biddick, K., Bonazzi, V., Brandon, R., Cargill, M., Chandramouliswaran, I., Charlab, R., Chaturvedi, K., Deng, Z., Di Francesco, V., Dunn, P., Eilbeck, K., Evangelista, C., Gabrielian, A.E., Gan, W., Ge, W., Gong, F., Gu, Z., Guan, P., Heiman, T.J., Higgins, M.E., Ji, R.R., Ke, Z., Ketchum, K.A., Lai, Z., Lei, Y., Li, Z., Li, J., Liang, Y., Lin, X., Lu, F., Merkulov, G.V., Milshina, N., Moore, H.M., Naik, A.K., Narayan, V.A., Neelam, B., Nusskern, D., Rusch, D.B., Salzberg, S., Shao, W., Shue, B., Sun, J., Wang, Z., Wang, A., Wang, X., Wang, J., Wei, M., Wides, R., Xiao, C., Yan, C., Yao, A., Ye, J., Zhan, M., Zhang, W., Zhang, H., Zhao, Q., Zheng, L., Zhong, F., Zhong, W., Zhu, S., Zhao, S., Gilbert, D., Baumhueter, S., Spier, G., Carter, C., Cravchik, A., Woodage, T., Ali, F., An, H., Awe, A., Baldwin, D., Baden, H., Barnstead, M., Barrow, I., Beeson, K., Busam, D., Carver, A., Center, A., Cheng, M.L., Curry, L., Danaher, S., Davenport, L., Desilets, R., Dietz, S., Dodson, K., Doup, L., Ferriera, S., Garg, N., Gluecksmann, A., Hart, B., Haynes, J., Haynes, C., Heiner, C., Hladun, S., Hostin, D., Houck, J., Howland, T., Ibegwam, C., Johnson, J., Kalush, F., Kline, L., Koduru, S., Love, A., Mann, F., May, D., McCawley, S., McIntosh, T., McMullen, I., Moy, M., Moy, L., Murphy, B., Nelson, K., Pfannkoch, C., Pratts, E., Puri, V., Qureshi, H., Reardon, M., Rodriguez, R., Rogers, Y.H., Romblad, D., Ruhfel, B., Scott, R., Sitter, C., Smallwood, M., Stewart, E., Strong, R., Suh, E., Thomas, R., Tint, N.N., Tse, S., Vech, C., Wang, G., Wetter, J., Williams, S., Williams, M., Windsor, S., Winn-Deen, E., Wolfe, K., Zaveri, J., Zaveri, K., Abril, J.F., Guigo, R., Campbell, M.J., Sjolander, K.V., Karlak, B., Kejariwal, A., Mi, H., Lazareva, B., Hatton, T., Narechania, A., Diemer, K., Muruganujan, A., Guo, N., Sato, S., Bafna, V., Istrail, S., Lippert, R., Schwartz, R., Walenz, B., Yooseph, S., Allen, D., Basu, A., Baxendale, J., Blick, L., Caminha, M., Carnes-Stine, J., Caulk, P., Chiang, Y.H., Coyne, M., Dahlke, C., Mays, A., Dombroski, M., Donnelly, M., Ely, D., Esparham, S., Fosler, C., Gire, H., Glanowski, S., Glasser, K., Glodek, A., Gorokhov, M., Graham, K., Gropman, B., Harris, M., Heil, J., Henderson, S., Hoover, J., Jennings, D., Jordan, C., Jordan, J., Kasha, J., Kagan, L., Kraft, C., Levitsky, A., Lewis, M., Liu, X., Lopez, J., Ma, D., Majoros, W., McDaniel, J., Murphy, S., Newman, M., Nguyen, T., Nguyen, N., Nodell, M., Pan, S., Peck, J., Peterson, M., Rowe, W., Sanders, R., Scott, J., Simpson, M., Smith, T., Sprague, A., Stockwell, T., Turner, R., Venter, E., Wang, M., Wen, M., Wu, D., Wu, M., Xia, A., Zandieh, A. and Zhu, X. (2001) The sequence of the human genome. Science, 1304-1351. doi:/10.1126/science.1058040
[26] Meneses, A. (1999) 5HT system and cognition. Neuroscience & Biobehavioral Reviews, 23, 1111-1125. doi:/10.1016/S0149-7634(99)00067-6
[27] Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P. and McKernan, K. (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860-921. doi:/10.1038/35057062
[28] O’Dowd, B.F., Ji, X., Alijaniaram, M., Nguyen, T. and George S.R. (2006) A novel drug screening assay for G protein-coupled receptors. In: Rognan, D., Mannhold, R., Kubinyi, H. and Folkers, G., Eds., Ligand Design for G Protein-Coupled Receptors (Methods and Principles in Medicinal Chemistry), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 51-60.
[29] Baldwin, J.M. (1993) The probable arrangement of the helices in G protein-coupledreceptors. The EMBO Journal, 12, 1693-1703.
[30] Grigorieff, N., Ceska, T.A., Downing, K.H., Baldwin, J.M., Henderson, R. (1996). Electron-crystallographic refinement of the structure of bacteriorhodopsin. Journal of Molecular Biology, 259, 393-421. doi:/10.1006/jmbi.1996.0328
[31] Kimura, Y., Vassylyev, D.G., Miyazawa, A., Kidera, A., Matsushima, M., Mitsuoka, K., Murata, K., Hirai, T. and Fujiyoshi, Y. (1997). Surface of bacteriorhodopsin revealed by high-resolution electron crystallography. Nature, 389, 206-211. doi:/10.1038/38323
[32] Pebay-Peyroula, E., Rummel, G., Rosenbusch, J.P. and Landau, E.M. (1997) X-ray structure of bacteriorhodopsin at 2.5 angstroms from microcrystals grown in lipidic cubic phases. Science, 277, 1676-1681. doi:/10.1126/science.277.5332.1676
[33] Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Trong, I.L., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M. and Miyano, M. (2000) Crystal structure of rhodopsin: A G proteincoupled receptor. Science, 289, 739-745. doi:/10.1126/science.289.5480.739
[34] Rasmussen, S.G., Choi, H.J., Rosenbaum, D.M., Kobilka, T.S., Thian, F.S., Edwards, P.C., Burghammer, M., Ratnala, V.R., Sanishvili, R., Fischetti, R.F., Schertler, G.F., Weis, W.I. and Kobilka, B.K. (2007) Crystal structure of the human β2-adrenergic G-protein-coupled receptor. Nature, 450, 383-387. doi:/10.1038/nature06325
[35] Cherezov, V., Rosenbaum, D.M., Hanson, M.A., Rasmussen, S.G., Thian, F.S., Kobilka, T.S., Choi, H.J., Kuhn, P., Weis, W.I., Kobilka, B.K. and Stevens, R.C. (2007) High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science, 318, 1258-1265. doi:/10.1126/science.1150577
[36] Drews, J. (1996) Genomic sciences and the medicine of tomorrow. Nature Biotechnology, 14, 1516-1518. doi:/10.1038/nbt1196-1516
[37] Yang, J. and Liu, C.Q. (2000) Molecular modeling on human CCR5 receptors and complex with CD4 antigens and HIV-1envelope Glycoprotein gp120. Acta Pharmacologica Sinica, 20, 29-34.
[38] Yang, J., Zhang, Y.W., Huang, J.F., Zhang, Y.P. and Liu, C.Q. (2000) Structure analysis of CCR5 from human and primates. Journal of Molecular Structure: Theochem, 505, 199-210. doi:/10.1016/S0166-1280(99)00393-0
[39] Yang, J. and Hua, W.Y. (1996). Basic pharmacophore for some antithrombotic agents with combined thromboxane receptor antagonists (TXRA)/thromboxine synthase inhibitor (TXSI) activities. Drug Development Research, 39, 197-200. doi:/10.1002/(SICI)1098-2299(199610)39:2<197::AID-DDR14>3.0.CO;2-9
[40] Zhan, C.Y., Yang, J., Dong, X.C. and Wang, Y.L. (2007) Molecular modeling of purinergic receptor P2Y12 and interaction with its antagonists. Journal of Molecular Graphics and Modelling, 26, 20-31. doi:/10.1016/j.jmgm.2006.09.006
[41] Xiao, Y.D., Harris, R., Bayram, E., Santago II, P. and Schmitt, J.D. (2006) Supervised self-organizing maps in drug discovery. 2. Improvements in descriptor selection and model validation. Journal of Chemical Information and Modeling, 46, 137-144. doi:/10.1021/ci0500841
[42] Yang, J., Dong, X.C. and Leng, Y. (2006) Application of FTTP to alpha-helix or beta-strand motifs. Journal of Theoretical Biology, 242, 199-219. doi:/10.1016/j.jtbi.2006.02.014
[43] Yang, J., Dong, X.C. and Leng, Y. (2006) Conformation biases of amino acids based on tripeptide microenvironment from PDB database. Journal of Theoretical Biology, 240, 374-384. doi:/10.1016/j.jtbi.2005.09.025
[44] Yu, J.M., Li, D.D., Xu, Z.Q., Cheng, W.X., Zhang, Q., Li, H.Y., Cui, S.X., Miao-Jin, Yang, S.H., Fang, Z.Y. and Duan, Z.J. (2008) Human bocavirus infection in children hospitalized with acute gastroenteritis in China. Journal of Clinical Virology, 42, 280-285. doi:/10.1016/j.jcv.2008.03.032
[45] Steiger, N.M., Lada, E.K., Wilson, J.R., Alexopoulos, C., Goldsman, D. and Zouaoui, F. (2002) ASAP2: An Improved Batch Means Procedure for Simulation Output Analysis. In: Yücesan, E., Chen, C.-H., Snowdon, J.L. and Charnes, J.M., Eds., Proceedings of the 2002 Winter Simulation Conference, Piscataway, New Jersey, 336344.
[46] Attwood, T.K., Croning, M.D. and Gaulton, A. (2002) Deriving structural and functional insights from a ligandbased hierarchical classification of G protein-coupled receptors. Protein Engineering, 15, 7-12. doi:/10.1093/protein/15.1.7
[47] Huang, J.H., Cao, D.S., Yan, J., Xu, Q.S., Hu, Q.N. and Liang, Y.Z. (2012) Using core hydrophobicity to identify phosphorylation sites of human G protein-coupled receptors. Biochimie, 94, 1697-1704. doi:/10.1016/j.biochi.2012.03.022
[48] Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. doi:/10.1126/science.1075762
[49] Pitcher, J.A., Freedman, N.J. and Lefkowitz, R.J. (1998) G protein-coupled receptor kinases. Annual Review of Biochemistry, 67, 653-692. doi:/10.1146/annurev.biochem.67.1.653
[50] Tobin, A.B., Butcher, A.J. and Kong, K.C. (2008) Location, location, location site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signaling. Trends in Pharmacological Sciences, 29, 413-420. doi:/10.1016/
[51] Hauser, F., Cazzamali, G., Williamson, M., Blenau, W. and Grimmelikhuijzen, J.P. (2006) A review of neurohormone GPCRs present in the fruitfly Drosophila melanogaster and the honey bee Apis mellifera. Progress in Neurobiology, 80, 1-19. doi:/10.1016/j.pneurobio.2006.07.005
[52] Meyer, J.M., Ejendal, K.F., Avramova, L.V., GarlandKuntz, E.E., Giraldo-Calderón, G.I., Brust, T.F., Watts, V.J. and Hill, C.A. (2012) A “genome-to-lead” approach for insecticide discovery: Pharmacological characterization and screening of Aedes aegypti D(1)-like dopamine receptors. PLOS Neglected Tropical Diseases 6, e1478. doi:/10.1371/journal.pntd.0001478
[53] Gamo, F.J., Sanz, L.M., Vidal, J., de Cozar, C., Alvarez, E., Lavandera, J.L., Vanderwall, D.E., Green, D,V., Kumar, V., Hasan, S., Brown, J.R., Peishoff, C.E., Cardon, L.R. and Garcia-Bustos, J.F. (2010) Thousands of chemical starting points for antimalarial lead identification. Nature, 465, 305-312. doi:/10.1038/nature09107
[54] Hill, C.A., Fox, A.N., Pitts, R.J., Kent, L.B., Tan, P.L., Chrystal, M.A., Cravchik, A., Collins, F.H., Robertson, H.M. and Zwiebel, L.J. (2002) G protein-coupled receptors in Anopheles gambiae. Science, 298, 176-178. doi:/10.1126/science.1076196
[55] Gruber, C.W., Muttenthaler, M. and Freissmuth, M. (2010) Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors. Current Pharmaceutical Design, 16, 3071-3088. doi:/10.2174/138161210793292474
[56] Janovick, J.A., Park, B.S. and Conn, P.M. (2011) Therapeutic rescue of misfolded mutants: Validation of primary high throughput screens for identification of pharmacoperone drugs. PLoS One, 6, e22784. doi:/10.1371/journal.pone.0022784
[57] Janovick, J.A., Patny, A., Mosley, R., Goulet, M.T., Altman, M.D., Rush 3rd, T.S., Cornea. A. and Conn, P.M. (2009) Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: The GnRH receptor. Molecular Endocrinology, 23, 157-168. doi:/10.1210/me.2008-0384
[58] Janovick, J.A., Maya-Nunez, G. and Conn, P.M. (2002) Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific proteinfolding template: misrouted proteins as a novel disease etiology and therapeutic target. The Journal of Clinical Endocrinology & Metabolism, 87, 3255-3262. doi:/10.1210/jc.87.7.3255
[59] Galietta, L.J., Springsteel, M.F., Eda, M., Niedzinski, E.J., By, K., Haddadin, M.J., Kurth, M.J., Nantz, M.H. and Verkman, A.S. (2001) Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. The Journal of Biological Chemistry, 276, 19723-19728. doi:/10.1074/jbc.M101892200
[60] Ulloa-Aguirre, A., Janovick, J.A., Leanos-Miranda, A. and Conn, P.M. (2003) Misrouted cell surface receptors as a novel disease aetiology and potential therapeutic target: The case of hypogonadotropic hypogonadism due to gonadotropin-releasing hormone resistance. Expert Opinion on Therapeutic Targets, 7, 175-185. doi:/10.1517/14728222.7.2.175
[61] Bernier, V., Lagace, M., Bichet, D.G. and Bouvier, M. (2004) Pharmacological chaperones: Potential treatment for conformational diseases. Trends in Endocrinology & Metabolism, 15, 222-228. doi:/10.1016/j.tem.2004.05.003
[62] Noorwez, S.M., Malhotra, R., McDowell, J.H., Smith, K.A., Krebs, M.P. and Kaushal, S. (2004) Retinoids assist the cellular folding of the autosomal dominant retinitis pigmentosa opsin mutant P23H. The Journal of Biological Chemistry, 279, 16278-16284. doi:/10.1074/jbc.M312101200
[63] Tveten, K., Holla, ?.L., Ranheim, T., Berge, K.E., Leren, T.P. and Kulseth, M.A. (2007) 4-Phenylbutyrate restores the functionality of a misfolded mutant low-density lipoprotein receptor. FEBS Journal, 274, 1881-1893. doi:/10.1111/j.1742-4658.2007.05735.x
[64] Benedek, G.B., Pande, J., Thurston, G.M. and Clark, J.I. (1999) Theoretical and experimental basis for the inhibition of cataract. Progress in Retinal and Eye Research, 18, 391-402. doi:/10.1016/S1350-9462(98)00023-8
[65] Heiser, V., Scherzinger, E., Boeddrich, A., Nordhoff, E., Lurz, R., Schugardt, N., Lehrach, H. and Wanker, E.E. (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: Implications for Huntington’s disease therapy. Proceedings of the National Academy of Sciences of the United States of America, 97, 6739-6744. doi:/10.1073/pnas.110138997
[66] Muchowski, P.J. and Wacker, J.L. (2005) Modulation of neurodegeneration by molecular chaperones. Nature Reviews Neuroscience, 6, 11-22. doi:/10.1038/nrn1587
[67] Forloni, G., Terreni, L., Bertani, I., Fogliarino, S., Invernizzi, R., Assini, A., Ribizzi, G., Negro, A., Calabrese, E., Volonté, M.A., Mariani, C., Franceschi, M., Tabaton, M. and Bertoli, A. (2002) Protein misfolding in Alzheimer's and Parkinson’s disease: Genetics and molecular mechanisms. Neurobiology of Aging, 23, 957-976. doi:/10.1016/S0197-4580(02)00076-3
[68] Peng, Y., Li, C., Chen, L., Sebti, S. and Chen, J. (2003) Rescue of mutant p53 transcription function by ellipticine. Oncogene, 22, 4478-4487. doi:/10.1038/sj.onc.1206777
[69] Janovick, J.A., Goulet, M., Bush, E., Greer, J., Wettlauffer, D.G. and Conn, P.M. (2003) Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. Journal of Pharmacology and Experimental Therapeutics, 305, 608- 614. doi:/10.1124/jpet.102.048454
[70] Costanzi, S. (2010) Modeling G Protein-Coupled Receptors: A concrete possibility. Chimica oggi, 28, 26-31.
[71] Sugahara, D., Kaji, H., Sugihara, K., Asano, M. and Narimatsu, H. (2012) Large-scale identification of target proteins of a glycosyltransferase isozyme by Lectin-IGOT- LC/MS, an LC/MS-based glycoproteomic approach. Scientific Reports, 2, 680. doi:/10.1038/srep00680
[72] Ying, S.Y., Chang, D.C. and Lin, S.L. (2013) The MicroRNA. Methods in Molecular Biology, 936, 1-19. doi:/10.1007/978-1-62703-083-0_1
[73] Coskun, M., Bjerrum, J.T., Seidelin, J.B. and Nielsen, O.H. (2012) MicroRNAs in inflammatory bowel disease— pathogenesis, diagnostics and therapeutics. World Journal of Gastroenterology, 18, 4629-4634. doi:/10.3748/wjg.v18.i34.4629

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.