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Structure-based drug discovery of ApoE4 inhibitors from the plant compounds

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Abstract

Apolipoprotein E4 (ApoE4) is a potential target for developing new therapeutics for Alzheimer’s disease (AD). Till now there is no drug available to inhibit this protein and cholinesterase inhibitor was given for almost all the AD patients. In this study, we have approached to identify the potential ApoE4 inhibitor from the plant compounds. Rigid docking study was performed for 18 plant compounds and 11 cholinesterase inhibitors. Based on the docking score, binding energy and number of hydrogen bonding curcumin posses the best scoring function. For further validation induce fit docking was performed and it also shows that curcumin binds to the same binding pocket of ApoE4 protein. Biological activity prediction reveals that curcumin has a potential therapeutic activity against AD. Pharmacokinetic properties of this compound are under the acceptable range. From the results we concluded that the plant compound curcumin could be a potential inhibitor of ApoE4 and it can control the AD.

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References

  • Ahmed ARH, MacGowan SH, Culpan D, Jones RW, Wilcock GK (1999) The -491A/T polymorphism of the Apolipoprotein E gene is associated with the ApoEepsilon4 allele and Alzheimer’s disease. Neurosci Lett 263:217–219

    Article  PubMed  CAS  Google Scholar 

  • Bales KR (2010) Brain lipid metabolism, apolipoprotein E and the pathophysiology of Alzheimer’s disease. Neuropharmacology 59:295–302

    Article  PubMed  CAS  Google Scholar 

  • Beckett LA, Harvey DJ, Gamst A, Donohue M, Kornak J, Zhang H, Kuo JH (2010) The Alzheimer’s disease neuroimaging initiative: annual change in biomarkers and clinical outcomes. Alzheimers Dement 6:257–264

    Article  PubMed  Google Scholar 

  • Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev Issue 1. Art. No.: CD001190. doi:10.1002/14651858.CD001190.pub2

  • Birks J, Evans JG, Iakovidou V, Tsolaki M (2009) Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. Issue 2. Art. No.: CD001191. doi:10.1002/14651858.CD001191.pub2

  • da Silva CHTDP, da Silva VB, Resende J, Rodrigues PF, Bononi FC, Benevenuto CG, Taft CA (2010) Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy. J Mol Graph Model 28:513–523

    Article  PubMed  Google Scholar 

  • Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno JG, Asher SW, Beaver C, Hamilton D, Bergman SM, Roger LF, Black SE, Carr S, Winchester T, Layne E, Clark C, Dexter J, DuBoff EA, Hendrie H, Caress J, Shatz R, Hanna GR, Brashear HR, Damgaard P, Donnelly K, Burch K, Homan RW, McSweeney AJ, Ann Barczak M, Mattes JA, Hermann AM, Mohr E, Mendis T, Roberts J, Begin L, Sampson M, Ott BR, Lannon MC, Prendergast JJ, Madan S, Hanning R, Martinez W, Stone R, Winner P, Zuniga J, Mate LJ, Ehlert BJ, Lessard C, Seltze B, Taylor JR, Calabrese VP, Harkins SW, Weis SJ, Slade W, Sommer BR, Wichter M, Schwartz M, Eastman J, Thein SG Jr, Williams G, Dewar JA, Foster NL, Bluemlein LA, Gelb DJ, Berent S, Giordani B, Baron BA, Myers S (1992) A controlled trial of tacrine in Alzheimer’s Disease. JAMA 268:2523–2529

    Article  PubMed  CAS  Google Scholar 

  • Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy. J Med Chem 47:1739–1749

    Article  PubMed  CAS  Google Scholar 

  • Halgren TA, Murphy RB, Friesne RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759

    Article  PubMed  CAS  Google Scholar 

  • Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, Huang Y (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci USA 100:10966–10971

    Article  PubMed  CAS  Google Scholar 

  • Hayes JM, Stein M, Weiser JR (2004) Accurate calculations of ligand binding free energies: chiral separation with enantioselective receptors. J Phys Chem A 108:3572–3580

    Article  CAS  Google Scholar 

  • Huang S, Li J, Sun L, Ye J, Fleisher A, Wu T, Chen K, Reiman E (2010) Learning brain connectivity of Alzheimer’s disease by sparse inverse covariance estimation. Neuroimage 50:935–949

    Article  PubMed  Google Scholar 

  • Khorana N, Markmee S, Ingkaninan K, Ruchirawat S, Kitbunnadaj R, Pullagurla MR (2009) Evaluation of a new lead for acetylcholinesterase inhibition. Med Chem Res 18(3):231–241

    Article  CAS  Google Scholar 

  • Kie H, van Robert R, Nicolaas PLGV (2009) Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement 5:348–360

    Article  Google Scholar 

  • Lagunin A, Stepanchikova A, Filimonov D, Poroikov V (2000) PASS: prediction of activity spectra for biologically active substances. Bioinformatics 16:747–748

    Article  PubMed  CAS  Google Scholar 

  • Lauria A, Ippolito M, Almerico AM (2009) Inside the Hsp90 inhibitors binding mode through induced fit docking. J Mol Graph Model 27:712–722

    Article  PubMed  CAS  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25

    Article  CAS  Google Scholar 

  • Lukiw WJ, Pappolla M, Pelaez RP, Bazan NG (2005) Alzheimer’s disease—a dysfunction in cholesterol and lipid metabolism. Cell Mol Neurobiol 25:475–483

    Article  PubMed  CAS  Google Scholar 

  • Mei Z, Zhang F, Tao L, Zheng W, Cao Y, Wang Z, Tang S, Le K, Chen S, Pi R, Liu P (2009) Cryptotanshinone, a compound from Salvia miltiorrhiza modulates amyloid precursor protein metabolism and attenuates beta-amyloid deposition through upregulating alpha-secretase in vivo and in vitro. Neurosci Lett 452:90–95

    Article  PubMed  CAS  Google Scholar 

  • Mishra S, Palanivelu K (2008) The effect of curcumin (turmeric) on Alzheimer’s disease: an overview. Ann Indian Acad Neurol 11:13–19

    Article  PubMed  Google Scholar 

  • Poirier J (2005) Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer’s disease. Neurobiol Aging 26:355–361

    Article  PubMed  CAS  Google Scholar 

  • Poroikov VV, Filimonov DA, Ihlenfeldt WD, Gloriozova TA, Lagunin AA, Borodina YV, Stepanchikova AV, Nicklaus MC (2002) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43:228–236

    Google Scholar 

  • QikProp (2009) version 3.1, Schrödinger, LLC, New York

  • Refolo L, Fillit H (2004) Apolipoprotein E4 as a target for developing new therapeutics for Alzheimer’s disease. J Mol Neurosci 23:151–155

    Article  PubMed  CAS  Google Scholar 

  • Reiman EM, Chen K, Caselli RJ, Alexander GE, Bandy D, Adamson JL, Lee W, Cannon A, Stephan EA, Stephan DA, Papassotiropoulos A (2008) Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer’s-affected brain regions. Neuroimage 40:1214–1221

    Article  PubMed  Google Scholar 

  • Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset alzheimer disease. Proc Natl Acad Sci USA 90:9649–9653

    Article  PubMed  CAS  Google Scholar 

  • Sengupta D, Verma D, Naik PK (2007) Docking mode of delvardine and its analogues into the p66 domain of HIV-1 reverse transcriptase: screening using molecular mechanics-generalized born/surface area and absorption, distribution, metabolism and excretion properties. J Biosci 32(7):1307–1316

    Article  PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset alzheimer disease. Proc Natl Acad Sci USA 90:8098–8102

    Article  PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, Roses AD (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci USA 91:11183–11186

    Article  PubMed  CAS  Google Scholar 

  • Tsuyoshi H, Kenjiro O, Masahito Y (2010) Curcumin and Alzheimer’s disease. CNS Neurosci Ther 16:285–297. doi:10.1111/j.1755-5949.2010.00147.x

    Article  Google Scholar 

  • Veera Venkata Ratnam B, Juan T, David W, Olga P, Jessica W, Kathy C, Norman JH (2009) ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer’s but not normal brain. Neurobiol Aging 30:591–599

    Article  Google Scholar 

  • Wang H, Aslanian R, Madison VS (2008) Induced-fit docking of mometasone furoate and further evidence for glucocorticoid receptor 17alpha pocket flexibility. J Mol Graph Model 27:512–521

    Article  PubMed  CAS  Google Scholar 

  • Weiner MW, Aisen PS, Jack CR Jr, Jagust WJ, Trojanowski JQ, Shaw L, Saykin AJ, Morris JC, Cairns N, Beckett LA, Toga A, Green R, Walter S, Soares H, Snyder P, Siemers E, Potter W, Cole PE, Schmidt M (2010) The Alzheimer’s disease neuroimaging initiative: progress report and future plans. Alzheimers Dement 6:202–211

    Article  PubMed  Google Scholar 

  • Weisgraber KH, Mahley RW (1996) Human apolipoprotein E: the Alzheimer’s disease connection. FASEB J 10:1485–1494

    PubMed  CAS  Google Scholar 

  • Xu PT, Li Y, Qin XJ, Scherzer CR, Xu H, Schmechel DE, Hulette CM, Ervin J, Gullans SR, Haines J, Pericak-Vance MA, Gilbert JR (2006) Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease. Neurobiol Dis 21:256–275

    Article  PubMed  CAS  Google Scholar 

  • Zarotsky V, Sramek JJ, Cutler NR (2003) Galantamine hydrobromide: an agent for Alzheimer’s disease. Am J Health Syst Pharm 60:446–452

    PubMed  CAS  Google Scholar 

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Acknowledgment

Authors like to thank Department of Bioinformatics, Alagappa University, Karaikudi, India for the support and facility provided for this study.

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Authors and Affiliations

  1. Department of Bioinformatics, Alagappa University, Karaikudi, 630 003, Tamil Nadu, India

    Kh. Dhanachandra Singh, M. Karthikeyan & P. Kirubakaran

  2. Department of Bioinformatics, Dr. G R Damodaran College of Science, Coimbatore, 641 014, Tamil Nadu, India

    V. Sathya & S. Nagamani

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  1. Kh. Dhanachandra Singh
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  2. M. Karthikeyan
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  3. P. Kirubakaran
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  4. V. Sathya
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  5. S. Nagamani
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Correspondence to M. Karthikeyan.

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Dhanachandra Singh, K., Karthikeyan, M., Kirubakaran, P. et al. Structure-based drug discovery of ApoE4 inhibitors from the plant compounds. Med Chem Res 21, 825–833 (2012). https://doi.org/10.1007/s00044-011-9595-3

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