山国到技论文在线 http://www.paper.edu.cn three-point pharmacophore model, the distances of R-Al, R-A2, and ArA2 are 3.96, 5.04, and 4.28 A respectively. The resulting structural information provide an exquisite understanding of their mechanism of interaction within non-ATP binding site of GSK-3B, and the finding of the common properties shared by such pharmacological inhibitors could be helpful for further optimization of these potent drug candidates Acknowledgement le gratefully acknowledge the financial support from Specialized Research Fund for the doctoral Program of Higher Education (SRFDP, No. 20070246089), Chinese Ministry of Education, Youth Science Foundation of Fudan University and Youth Fund of School of Pharmacy, Fudan University References 1. Lee, J Kim, M.S. The role of GsK3 in glucose homeostasis and the development of insulin resistance Diabetes Res. Clin Pract. 2007, 77 Suppl 1, $49-57 2. Frojdo, S; Vidal, H ; Pirola, L. Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Biochim. Biophys. Acta. 2009, 1792, 83-92 3. Hanger, D. P; Hughes, K, Woodgett, J. R; Brion, J. P, Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimers disease-like phosphorylation of tau generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 1992, 147, 58-62. 4. Hernandez, F, Avila, J. The role of glycogen synthase kinase 3 in the early stages of Alzheimers' disease FEBS Lett. 2008 5. Martin, L, Magnaudeix, A Esclaire, F. Yardin, C. Terro, F. Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A Brain res.2009,1252,66-75 6. Gould, T D; Zarate, C. A, Manji, H. K. Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. Clin Psychiatry 2004, 65, 10-21 7. Alonso, M ; Martinez, A. GSK-3 inhibitors: discoveries and developments. Curr. Med. Chem. 2004, 11 755-63 8. Martinez, A. Preclinical efficacy on GSK-3 inhibitors: towards a future generation of powerful drugs. Med. Res.Rev.2008,28,773-96 9. Cohen, P. Goedert, M. GSK3 inhibitors: development and therapeutic potential. Nature Reviews Drug Discover2004,3,479-487 10. Wagman, A S, Johnson, K. W, Bussiere, D. E. Discovery and development of GsK3 inhibitors for the treatment of type 2 diabetes. Current Pharmaceutical Design 2004, 10, 1105-1137 rame S ; Zheleva, D. Targeting glycogen synthase kinase-3 in insulin signalling. Expert Opinion on Therapeutic Targets 2006, 10, 429-444 12. Hu, S, Begum, A. N, Jones, M.R.: Oh, M. S: Beech, w.K.: Begum, A. N, Jones, M.R. Beech, B. H Yang, F, Chen, P; Ubeda, O. J. Kim, P. C. Davies, P. Ma, Q; Cole, G. M; Frautschy, S. A. GSK3 inhibitors show benefits in an Alzheimers disease(AD) model of neurodegeneration but adverse effects in control animals Neurobiology of Disease 2009, 33, 193-206 13. Sun, X, Sato, S, Murayama, O: Murayama, M, Park, J. M ; Yamaguchi, H. Takashima, A. Lithium inhibits amy loid secretion in COs7 cells transfected with amyloid precursor protein C100. Neurosci. Left. 2002 321,61-64 14. Koh, S. H; Noh, M.Y. Kim, S.H. Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Research 2008, 1188, 254-262 15. Martinez, A, Alonso, M, Castro, A, Perez, C. Moreno, F J. First Non-ATP Competitive Glycogen Synthase Kinase 3B(GSK-3B)Inhibitors: Thiadiazolidinones (TDzD) as Potential Drugs for the Treatment of Alzheimers Disease. J. Med. Chem. 2002, 45. 1292-1299. 16. Conde, S; Perez, D. I, Martinez, A; Perez, C. Moreno, F J. Thienyl and Pher New Inhibitors of Glycogen Synthase Kinase(GSK-3 alpha) from a Library of Ce ol alhopuard seaming toes. Chem.2003,46,4631-4633 17. Martinez, A Alonso, M. Castro, A, Dorronsoro, I, Gelpi, J. L; Luque, F J, Perez, C, Moreno, F.J. SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 inhibitors. J. Med. Chem. 2005, 48, 7103-12 18. Castro, A, Encinas, A, Gil, C; Brase, S, Porcal, W, Perez, C ; Moreno, F. J, Martinez, A. Non-ATP competitive glycogen synthase kinase 3[beta](GSK-3 [beta)inhibitors: Study of structural requirements for thiadiazolidinone derivatives. Bioorganic Medicinal Chemistry 2008, 16, 495-510 19. Bertrand, J. A, Thieffine, S, Vulpetti, A; Cristiani, C. Valsasina, B ; Knapp, S, Kalisz, H. M., Flocco, M Structural characterization of the gsK-3 beta active site using selective and non-selective ATP-mi J.Mol.Biol.2003,333,393-407. 0. Stewart, JJ MOPAC: a semiempirical molecular orbital program. J Comput Aided Mol Des 1990, 4, 1-105 1. Jakalian, A, Bush, B. L, Jack, D. B, Bayly, C. I. Fast, Efficient Generation of High-Quality Atomi- 8 - three-point pharmacophore model, the distances of R–A1, R–A2, and A1–A2 are 3.96, 5.04, and 4.28 A˚, respectively. The resulting structural information provide an exquisite understanding of their mechanism of interaction within non-ATP binding site of GSK-3β, and the finding of the common properties shared by such pharmacological inhibitors could be helpful for further optimization of these potent drug candidates. Acknowledgement We gratefully acknowledge the financial support from Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, No. 20070246089), Chinese Ministry of Education, Youth Science Foundation of Fudan University and Youth Fund of School of Pharmacy, Fudan University. References: 1. Lee, J.; Kim, M. S. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res. Clin. Pract. 2007, 77 Suppl 1, S49-57. 2. Frojdo, S.; Vidal, H.; Pirola, L. Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Biochim. Biophys. Acta. 2009, 1792, 83-92. 3. Hanger, D. P.; Hughes, K.; Woodgett, J. R.; Brion, J. P.; Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 1992, 147, 58-62. 4. Hernandez, F.; Avila, J. The role of glycogen synthase kinase 3 in the early stages of Alzheimers' disease. FEBS Lett. 2008, 582, 3848-54. 5. Martin, L.; Magnaudeix, A.; Esclaire, F.; Yardin, C.; Terro, F. Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain Res. 2009, 1252, 66-75. 6. Gould, T. D.; Zarate, C. A.; Manji, H. K. Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. J Clin Psychiatry 2004, 65, 10-21. 7. Alonso, M.; Martinez, A. GSK-3 inhibitors: discoveries and developments. Curr. Med. Chem. 2004, 11, 755-63. 8. Martinez, A. Preclinical efficacy on GSK-3 inhibitors: towards a future generation of powerful drugs. Med. Res. Rev. 2008, 28, 773-96. 9. Cohen, P.; Goedert, M. GSK3 inhibitors: development and therapeutic potential. Nature Reviews Drug Discovery 2004, 3, 479-487. 10. Wagman, A. S.; Johnson, K. W.; Bussiere, D. E. Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Current Pharmaceutical Design 2004, 10, 1105-1137. 11. Frame, S.; Zheleva, D. Targeting glycogen synthase kinase-3 in insulin signalling. Expert Opinion on Therapeutic Targets 2006, 10, 429-444. 12. Hu, S.; Begum, A. N.; Jones, M. R.; Oh, M. S.; Beech, W. K.; Begum, A. N.; Jones, M. R.; Beech, B. H.; Yang, F.; Chen, P.; Ubeda, O. J.; Kim, P. C.; Davies, P.; Ma, Q.; Cole, G. M.; Frautschy, S. A. GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiology of Disease 2009, 33, 193-206. 13. Sun, X.; Sato, S.; Murayama, O.; Murayama, M.; Park, J. M.; Yamaguchi, H.; Takashima, A. Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci.Lett. 2002, 321, 61-64 14. Koh, S. H.; Noh, M. Y.; Kim, S. H. Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Research 2008, 1188, 254-262. 15. Martinez, A.; Alonso, M.; Castro, A.; Perez, C.; Moreno, F. J. First Non-ATP Competitive Glycogen Synthase Kinase 3β(GSK-3β) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease. J. Med. Chem. 2002, 45, 1292-1299. 16. Conde, S.; Perez, D. I.; Martinez, A.; Perez, C.; Moreno, F. J. Thienyl and Phenyl alhpa-Halomethyl Ketones: New Inhibitors of Glycogen Synthase Kinase (GSK-3 alpha) from a Library of Compound Searching. J. Med. Chem. 2003, 46, 4631-4633. 17. Martinez, A.; Alonso, M.; Castro, A.; Dorronsoro, I.; Gelpi, J. L.; Luque, F. J.; Perez, C.; Moreno, F. J. SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 inhibitors. J. Med. Chem. 2005, 48, 7103-12. 18. Castro, A.; Encinas, A.; Gil, C.; Bräse, S.; Porcal, W.; Pérez, C.; Moreno, F. J.; Martínez, A. Non-ATP competitive glycogen synthase kinase 3[beta] (GSK-3[beta]) inhibitors: Study of structural requirements for thiadiazolidinone derivatives. Bioorganic & Medicinal Chemistry 2008, 16, 495-510. 19. Bertrand, J. A.; Thieffine, S.; Vulpetti, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H. M.; Flocco, M. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J. Mol. Biol. 2003, 333, 393-407. 20. Stewart, J. J. MOPAC: a semiempirical molecular orbital program. J Comput Aided Mol Des 1990, 4, 1-105. 21. Jakalian, A.; Bush, B. L.; Jack, D. B.; Bayly, C. I. Fast, Efficient Generation of High-Quality Atomic 中国科技论文在线 http://www.paper.edu.cn