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Medicinal Chemistry Research

, Volume 23, Issue 12, pp 5141–5148 | Cite as

Insight into the anti-amyloidogenic activity of polyphenols and its application in virtual screening of phytochemical database

  • Sandipan Chakraborty
  • Soumalee Basu
Original Research

Abstract

Alzheimer’s Disease (AD) is the most frequent form of neurodegenerative disorder pathologically characterized by the presence of aggregates of Aβ in the region of the brain involved in memory and cognition. Polyphenols commonly found in several daily consumed food items and beverages have been demonstrated to inhibit Aβ aggregation using various biophysical or cell culture-based techniques. Here, insight into the anti-amyloidogenic activity of polyphenols has been explored using 2-D QSAR methodology implemented in CODESSA packages. Interestingly, hydrophobic interactions emerge as a significant descriptor for the recognition of amyloid fibril by polyphenols. Thus, it may be interpreted that highly potent polyphenols capably bind within the hydrophobic core region of the amyloid fibril and, thereby, destabilize the fibril by interrupting the hydrophobic interactions present within the fibril. Highly branched substituents and substituents with high degree of conformational flexibility on the polyphenolic structural scaffold enhance the fibril-destabilizing activity of compounds. In addition, specific electrostatic interaction between amyloid fibril and polyphenol plays a crucial role for the recognition of the fibril by polyphenols. The “application domain” of the derived QSAR model also has been defined, and the derived model has been used to screen a small in-house developed phytochemicals database comprising 200 compounds. 59 phytochemicals have been predicted as highly active anti-amyloidogenic phytochemicals. The modeling strategy is an efficient way to reduce the chemical search space and can selectively mine novel lead anti-amyloidogenic molecule from large chemical databases.

Keywords

Amyloid beta inhibitor Polyphenols QSAR Application domain Phytochemicals Virtual screening 

Notes

Acknowledgement

Soumalee Basu acknowledges financial support from the Department of Science and Technology, Govt. of West Bengal.

Supplementary material

44_2014_1081_MOESM1_ESM.doc (102 kb)
Supplementary material 1 (DOC 101 kb)

References

  1. AMPAC 9.0, © Semichem, 7128 Summit, Shawnee, KS 66216. 1994Google Scholar
  2. Abd El Mohsen MM, Kuhnle G, Rechner AR, Schroeter H, Rose S, Jenner P, Rice-Evans CA (2002) Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 33:1693–1702CrossRefPubMedGoogle Scholar
  3. Bastianetto S, Zheng WH, Quirion R (2000) Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. Br J Pharmacol 131:711–720PubMedCentralCrossRefPubMedGoogle Scholar
  4. Bastianetto S, Krantic S, Quirion R (2008) Polyphenols as potential inhibitors of amyloid aggregation and toxicity: possible significance to Alzheimer’s disease. Mini Rev Med Chem 8:429–435CrossRefPubMedGoogle Scholar
  5. Bush AI (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 23:1031–1038CrossRefPubMedGoogle Scholar
  6. Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI (2001) The green tea polyphenol (−)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 70:603–614CrossRefPubMedGoogle Scholar
  7. CODESSA [computer program] Version 2.7.16. (1995) Comprehensive descriptor for structure and statistical analysis. Copyright center of heterocyclic chemistry, University of Florida and institute of chemical physics, University of Tartu, Estonia and SemiChem IncGoogle Scholar
  8. Estus S, Tucker HM, van Rooyen C, Wright S, Brigham EF, Wogulis M, Rydel RE (1997) Aggregated amyloid-beta protein induces cortical neuronal apoptosis and concomitant “apoptotic” pattern of gene induction. J Neurosci 17:7736–7745PubMedGoogle Scholar
  9. Goodman Y, Steiner MR, Steiner SM, Mattson MP (1994) Nordihydroguaiaretic acid protects hippocampal neurons against amyloid betapeptide toxicity, and attenuates free radical and calcium accumulation. Brain Res 654:171–176CrossRefPubMedGoogle Scholar
  10. Hilbich C, Kisters-Woike B, Reed J, Masters CL, Beyreuther K (1992) Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J Mol Biol 20:460–473CrossRefGoogle Scholar
  11. Inanami O, Watanabe Y, Syuto B, Nakano M, Tsuji M, Kuwabara M (1998) Oral administration of (−)-catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radic Res 29:359–365CrossRefPubMedGoogle Scholar
  12. Hyperchem, Hypercube, Inc., USA, 2002Google Scholar
  13. Keller JN, Pang Z, Geddes JW, Begley JG, Germeyer A, Waeg G, Mattson MP (1997) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem 69:273–284CrossRefPubMedGoogle Scholar
  14. Kim MK, Choo IH, Lee HS, Woo JI, Chong Y (2007) 3D-QSAR of PET agents for imaging β -amyloid in Alzheimer’s Disease. Bull Korean Chem Soc 28:1231–1234CrossRefGoogle Scholar
  15. Lin GX, Koelsch SW, Downs D, Dashti A (2000) Human aspartic protease memapsin 2 cleaves the β-secretase site of Aβ-amyloid precursor protein. Proc Natl Acad Sci (U S A) 97:1456–1460CrossRefGoogle Scholar
  16. Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R (2005) 3D structure of Alzheimer’s amyloid-β (1–42) fibrils. Proc Natl Acad Sci (U S A) 102:17342–17347CrossRefGoogle Scholar
  17. Lundkvist J, Naslund J (2007) Gamma-secretase: a complex target for Alzheimers disease. Curr Opin Pharmacol 7:112–118CrossRefPubMedGoogle Scholar
  18. Mura E, Lanni C, Preda S, Pistoia F, Sarà M, Racchi M, Schettini G, Marchi M, Govoni S (2010) Amyloid: a disease target or a synaptic regulator affecting age-related neurotransmitter changes? Curr Pharm Des 16:672–683CrossRefPubMedGoogle Scholar
  19. Ono K, Hasegawa K, Yoshiike Y, Takashima A, Yamada M, Naiki H (2002) Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer’s beta amyloid fibrils in vitro. J Neurochem 81:434–440CrossRefPubMedGoogle Scholar
  20. Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87:172–181CrossRefPubMedGoogle Scholar
  21. Peng HW, Cheng FC, Huang YT, Chen CF, Tsai TH (1998) Determination of naringenin and its glucoronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography. J Chromatogr 714:369–374CrossRefGoogle Scholar
  22. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563:311–314CrossRefPubMedGoogle Scholar
  23. Pollack SJ, Sadler IIJ (1995) Sulfonated dyes attenuate the toxic effects of β-amyloid in a structure-specific fashion. Neurosci Lett 197:211–214CrossRefPubMedGoogle Scholar
  24. Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 67:27–37CrossRefPubMedGoogle Scholar
  25. Re F, Airoldi C, Zona C, Masserini M, Ferla BL, Quattrocchi N, Nicotra F (2010) Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer’s Disease. Curr Med Chem 17:2990–3006CrossRefPubMedGoogle Scholar
  26. Sabate R, Estelrich J (2005) Stimulatory and inhibitory effects of alkyl bromide surfactants on β-amyloid fibrillogenesis. Langmuir 21:6944–6949CrossRefPubMedGoogle Scholar
  27. Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6:487–498CrossRefPubMedGoogle Scholar
  28. Selkoe DJ (1994) Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer’s disease. Annu Rev Cell Biol 10:373–403CrossRefPubMedGoogle Scholar
  29. Shutenko Z, Henry Y, Pinard E, Seylaz J, Potier P, Berthet F, Girard P, Sercombe R (1999) Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem Pharmacol 57:199–208CrossRefPubMedGoogle Scholar
  30. Soto C (1999) Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease. Mol Med Today 5:343–350CrossRefPubMedGoogle Scholar
  31. Subramaniam R, Koppal T, Green M, Yatin S, Jordan B, Drake J, Butterfield DA (1998) The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide (25–35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer’s disease. Neurochem Res 23:1403–1410CrossRefPubMedGoogle Scholar
  32. Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M (2005) Inhibition of heparin-induced Tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 280:7614–7623CrossRefPubMedGoogle Scholar
  33. Tsai T-H, Chen Y-F (2000) Determination of unbound hesperetin in rat blood and brain by microdialysis coupled to microbore liquid chromatography. J Food Drug Anal 8:331–336Google Scholar
  34. Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) Review: alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130:184–208CrossRefPubMedGoogle Scholar
  35. Walsh DM, Selkoe DJ (2007) Aβ Oligomers—a decade of discovery. J Neurochem 101:1172–1184CrossRefPubMedGoogle Scholar
  36. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901CrossRefPubMedGoogle Scholar
  37. Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans CA (2003) Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem 85:180–192CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Saroj Mohan Institute of TechnologyGuptiparaIndia
  2. 2.School of Biotechnology & Biological SciencesWest Bengal University of TechnologyKolkataIndia
  3. 3.Department of MicrobiologyUniversity of CalcuttaKolkataIndia

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