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Molecular Docking and Design of Novel Heterodimers of Donepezil and Huperzine Fragments as Acetylcholinesterase Inhibitors 被引量:4

Molecular Docking and Design of Novel Heterodimers of Donepezil and Huperzine Fragments as Acetylcholinesterase Inhibitors
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摘要 To provide hints for the design of new acetylcholinesterase(ACh E) inhibitors with higher potency and specificity, the binding modes of novel heterodimers comprised of donepezil and huperzine A fragments with ACh E were explored by employing the docking simulations. The results show that the binding mode of S-17b(the most potent inhibitor in Ref. 2, i.e., Bioorg. Med. Chem. 2013, 21, 676-683) is clearly different from that of donepezil, while the binding modes of other heterodimers in Ref. 2 are the same as that of donepezil. In addition, based on the binding mode and structure modification of S-17 b, two novel inhibitors(S-17b1 and S-17bb1) with much higher inhibitory potency than S-17 b were obtained. Our design strategy was to replace the hupyridone moiety of S-17 b with the bulky group, and to replace the dimethoxyindanone moiety of S-17 b with more hydrophobic and bulky group with a highly positive charge, which would result in generating potent and selective AChE inhibitors. To provide hints for the design of new acetylcholinesterase(ACh E) inhibitors with higher potency and specificity, the binding modes of novel heterodimers comprised of donepezil and huperzine A fragments with ACh E were explored by employing the docking simulations. The results show that the binding mode of S-17b(the most potent inhibitor in Ref. 2, i.e., Bioorg. Med. Chem. 2013, 21, 676-683) is clearly different from that of donepezil, while the binding modes of other heterodimers in Ref. 2 are the same as that of donepezil. In addition, based on the binding mode and structure modification of S-17 b, two novel inhibitors(S-17b1 and S-17bb1) with much higher inhibitory potency than S-17 b were obtained. Our design strategy was to replace the hupyridone moiety of S-17 b with the bulky group, and to replace the dimethoxyindanone moiety of S-17 b with more hydrophobic and bulky group with a highly positive charge, which would result in generating potent and selective AChE inhibitors.
出处 《Chinese Journal of Structural Chemistry》 SCIE CAS CSCD 2016年第6期839-848,共10页 结构化学(英文)
基金 Supported by the Natural Science Foundation of Guangxi Province(Nos.2013GXNSFAA019019 and 2013GXNSFAA019041)
关键词 molecular docking acetylcholinesterase Alzheimer's disease molecular docking acetylcholinesterase Alzheimer's disease
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  • 1Lahiri DK, Farlow MR, Greig NH, Sambamurti K. Current drug targets for Alzheimer's disease treatment. Drug Dev Res 2002, 56: 267-81. 被引量:1
  • 2Silman I, Sussman JL. Acetylcholinesterase: "classical" and "nonclassical" functions andpharmacology. Curr Opin Pharmacol 2005, 5: 293-302. 被引量:1
  • 3Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat Struct Biol 1997, 4: 57-63. 被引量:1
  • 4Kryger G, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Struct 1999, 7: 297-307. 被引量:1
  • 5Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 1993, 90: 9031-5. 被引量:1
  • 6Harel M, Quinn DM, Nair HK, Silman I, Sussman JL. The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetvlcholinesterase J Am Chem Soc 1996,118: 2340-6. 被引量:1
  • 7Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett 1999, 463: 321-6. 被引量:1
  • 8Ravelli RB, Raves ML, Ren Z, Bourgeois D, Roth M, Kroon J, et al. Static Laue diffraction studies on acetylcholinesterase. Acta Crystallogr D Biol Crystallogr 1998, 54: 1359-66. 被引量:1
  • 9Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 1996, 16: 881-91. 被引量:1
  • 10Bartolini M, Bertucci C, Cavrini V, Andrisano V. Beta-amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 2003, 65: 407-16. 被引量:1

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