Skip to main content
SpringerLink
Log in

Computational Design of Multitarget Drugs Against Alzheimer’s Disease

  • Protocol
  • First Online:
Book cover Multi-Target Drug Design Using Chem-Bioinformatic Approaches

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

In the present review, the authors provide the basic background about the molecular targets implicated in the pathogenesis of Alzheimer’s disease. Furthermore, the authors review structure–activity relationships (SAR), 2D- and 3D-quantitative structure–activity relationships (QSAR), as well as other computational modeling studies performed on multitarget agents for Alzheimer’s disease.

The information provided includes chemical structures of multitarget agents and/or of hybrids acting on several molecular target enzymes implicated in the Alzheimer’s disease pathogenesis and information for the used computational techniques. This should be useful in the development of new multitarget drugs with clinical applicability in Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Mitra A, Dey B (2013) Therapeutic interventions in Alzheimer disease. In: Neurodegenerative diseases. InTech, London

    Google Scholar 

  2. Silva T, Reis J, Teixeira J, Borges F (2014) Alzheimer’s disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes. Ageing Res Rev 15:116–145. https://doi.org/10.1016/j.arr.2014.03.008

    Article  CAS  PubMed  Google Scholar 

  3. Cheng X, Zhang L, Lian Y-J (2015) Molecular targets in Alzheimer’s disease: from pathogenesis to therapeutics. Biomed Res Int 2015:760758

    PubMed  PubMed Central  Google Scholar 

  4. Grill JD, Cummings JL (2010) Novel targets for Alzheimer’s disease treatment. Expert Rev Neurother 10(5):711

    Article  CAS  Google Scholar 

  5. Kumar A, Nisha CM, Silakari C, Sharma I, Anusha K, Gupta N, Nair P, Tripathi T (2016) Current and novel therapeutic molecules and targets in Alzheimer's disease. J Formos Med Assoc 115(1):3–10. https://doi.org/10.1016/j.jfma.2015.04.001

    Article  CAS  PubMed  Google Scholar 

  6. Nicolotti O, Giangreco I, Introcaso A, Leonetti F, Stefanachi A, Carotti A (2011) Strategies of multi-objective optimization in drug discovery and development. Expert Opin Drug Discov 6(9):871–884. https://doi.org/10.1517/17460441.2011.588696

    Article  CAS  Google Scholar 

  7. Dobi K, Hajdu I, Flachner B, Fabo G, Szaszko M, Bognar M, Magyar C, Simon I, Szisz D, Lorincz Z, Cseh S, Dorman G (2014) Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors. Molecules 19(6):7008–7039. https://doi.org/10.3390/molecules19067008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG (2012) ZINC: a free tool to discover chemistry for biology. J Chem Inf Model 52(7):1757–1768. https://doi.org/10.1021/ci3001277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Irwin JJ, Shoichet BK (2005) ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 45(1):177–182. https://doi.org/10.1021/ci049714+

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sterling T, Irwin JJ (2015) ZINC 15—ligand discovery for everyone. J Chem Inf Model 55(11):2324–2337. https://doi.org/10.1021/acs.jcim.5b00559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44(D1):D1202–D1213. https://doi.org/10.1093/nar/gkv951

    Article  CAS  Google Scholar 

  12. Chemspider (2017) http://www.chemspider.com/

  13. ChEMBLdb (2017) Release 23. https://www.ebi.ac.uk/chembl/downloads

  14. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242. https://doi.org/10.1093/nar/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Artimo P, Jonnalagedda M, Arnold K, Baratin D, Csardi G, de Castro E, Duvaud S, Flegel V, Fortier A, Gasteiger E, Grosdidier A, Hernandez C, Ioannidis V, Kuznetsov D, Liechti R, Moretti S, Mostaguir K, Redaschi N, Rossier G, Xenarios I, Stockinger H (2012) ExPASy: SIB bioinformatics resource portal. Nucleic Acids Res 40(web server issue):W597–W603. https://doi.org/10.1093/nar/gks400

    Article  CAS  Google Scholar 

  16. Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341. https://doi.org/10.1016/j.ddtec.2004.11.007

    Article  CAS  Google Scholar 

  17. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26. https://doi.org/10.1016/S0169-409X(00)00129-0

    Article  CAS  Google Scholar 

  18. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53(7):2719–2740. https://doi.org/10.1021/jm901137j

    Article  CAS  PubMed  Google Scholar 

  19. Brus B, Kosak U, Turk S, Pislar A, Coquelle N, Kos J, Stojan J, Colletier JP, Gobec S (2014) Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor. J Med Chem 57(19):8167–8179. https://doi.org/10.1021/jm501195e

    Article  CAS  PubMed  Google Scholar 

  20. Messer WS Jr, Rajeswaran WG, Cao Y, Zhang HJ, el-Assadi AA, Dockery C, Liske J, O'Brien J, Williams FE, Huang XP, Wroblewski ME, Nagy PI, Peseckis SM (2000) Design and development of selective muscarinic agonists for the treatment of Alzheimer’s disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors. Pharm Acta Helv 74(2–3):135–140. https://doi.org/10.1016/S0031-6865(99)00026-6

    Article  CAS  PubMed  Google Scholar 

  21. Nordvall G, Hacksell U (1993) Binding-site modeling of the muscarinic m1 receptor: a combination of homology-based and indirect approaches. J Med Chem 36(8):967–976. https://doi.org/10.1021/jm00060a003

    Article  CAS  PubMed  Google Scholar 

  22. Messer WS Jr, Abuh YF, Liu Y, Periyasamy S, Ngur DO, Edgar MA, El-Assadi AA, Sbeih S, Dunbar PG, Roknich S, Rho T, Fang Z, Ojo B, Zhang H, Huzl JJ 3rd, Nagy PI (1997) Synthesis and biological characterization of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists. J Med Chem 40(8):1230–1246. https://doi.org/10.1021/jm960467d

    Article  CAS  PubMed  Google Scholar 

  23. Niu YY, Yang LM, Deng KM, Yao JH, Zhu L, Chen CY, Zhang M, Zhou JE, Shen TX, Chen HZ, Lu Y (2007) Quantitative structure-selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists. Bioorg Med Chem Lett 17(8):2260–2266. https://doi.org/10.1016/j.bmcl.2007.01.058

    Article  CAS  PubMed  Google Scholar 

  24. Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110(18):5959–5967. https://doi.org/10.1021/ja00226a005

    Article  CAS  Google Scholar 

  25. Wang Y, Chackalamannil S, Hu Z, Clader JW, Greenlee W, Billard W, Binch H, Crosby G, Ruperto V, Duffy RA, McQuade R, Lachowicz JE (2000) Design and synthesis of piperidinyl piperidine analogues as potent and selective M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 10(20):2247–2250. https://doi.org/10.1016/s0960-894x(00)00457-1

    Article  CAS  PubMed  Google Scholar 

  26. Nicolotti O, Pellegrini-Calace M, Altomar C, Carotti A, Carrieri A, Sanz F (2002) Ligands of neuronal nicotinic acetylcholine receptor (nAChR): inferences from the Hansch and 3-D quantitative structure-activity relationship (QSAR) models. Curr Med Chem 9(1):1–29. https://doi.org/10.2174/0929867023371463

    Article  CAS  PubMed  Google Scholar 

  27. Wei DQ, Sirois S, Du QS, Arias HR, Chou KC (2005) Theoretical studies of Alzheimer’s disease drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine (GTS-21) and its derivatives. Biochem Biophys Res Commun 338(2):1059–1064. https://doi.org/10.1016/j.bbrc.2005.10.047

    Article  CAS  PubMed  Google Scholar 

  28. Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835):269–276. https://doi.org/10.1038/35077011

    Article  CAS  PubMed  Google Scholar 

  29. Kombo DC, Mazurov AA, Strachan JP, Bencherif M (2013) Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with alpha4beta2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes. Bioorg Med Chem Lett 23(18):5105–5113. https://doi.org/10.1016/j.bmcl.2013.07.028

    Article  CAS  PubMed  Google Scholar 

  30. Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y (2005) Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J 24(20):3635–3646. https://doi.org/10.1038/sj.emboj.7600828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Catto M, Nicolotti O, Leonetti F, Carotti A, Favia AD, Soto-Otero R, Méndez-Álvarez E, Carotti A (2006) Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand-and target-based approaches. J Med Chem 49(16):4912–4925

    Article  CAS  Google Scholar 

  32. Speck-Planche A, Kleandrova V (2012) QSAR and molecular docking techniques for the discovery of potent monoamine oxidase B inhibitors: computer-aided generation of new rasagiline bioisosteres. Curr Top Med Chem 12(16):1734–1747. https://doi.org/10.2174/1568026611209061734

    Article  CAS  PubMed  Google Scholar 

  33. Di Pietro O, Alencar N, Esteban G, Viayna E, Szalaj N, Vazquez J, Juarez-Jimenez J, Sola I, Perez B, Sole M, Unzeta M, Munoz-Torrero D, Luque FJ (2016) Design, synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors. Bioorg Med Chem 24(20):4835–4854. https://doi.org/10.1016/j.bmc.2016.06.045

    Article  PubMed  Google Scholar 

  34. Esteban G, Allan J, Samadi A, Mattevi A, Unzeta M, Marco-Contelles J, Binda C, Ramsay RR (2014) Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease. Biochim Biophys Acta 1844(6):1104–1110. https://doi.org/10.1016/j.bbapap.2014.03.006

    Article  CAS  PubMed  Google Scholar 

  35. De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A (2005) Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc Natl Acad Sci U S A 102(36):12684–12689. https://doi.org/10.1073/pnas.0505975102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoang VH, Tran PT, Cui M, Ngo VT, Ann J, Park J, Lee J, Choi K, Cho H, Kim H, Ha HJ, Hong HS, Choi S, Kim YH (2017) Discovery of potent human glutaminyl cyclase inhibitors as anti-Alzheimer’s agents based on rational design. J Med Chem 60(6):2573–2590. https://doi.org/10.1021/acs.jmedchem.7b00098

    Article  CAS  PubMed  Google Scholar 

  37. Huang KF, Liaw SS, Huang WL, Chia CY, Lo YC, Chen YL, Wang AH (2011) Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. J Biol Chem 286(14):12439–12449. https://doi.org/10.1074/jbc.M110.208595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao L, Brinton RD (2006) Select estrogens within the complex formulation of conjugated equine estrogens (Premarin®) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer’s disease. BMC Neurosci 7(1):24

    Article  CAS  Google Scholar 

  39. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389(6652):753–758. https://doi.org/10.1038/39645

    Article  CAS  PubMed  Google Scholar 

  40. Cerpa W, Godoy JA, Alfaro I, Farias GG, Metcalfe MJ, Fuentealba R, Bonansco C, Inestrosa NC (2008) Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem 283(9):5918–5927. https://doi.org/10.1074/jbc.M705943200

    Article  CAS  PubMed  Google Scholar 

  41. Hanger DP, Noble W (2011) Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation. Int J Alzheimers Dis 2011:352805. https://doi.org/10.4061/2011/352805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cadigan KM, Waterman ML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4(11). https://doi.org/10.1101/cshperspect.a007906

    Article  Google Scholar 

  43. Zorn AM (2001) Wnt signalling: antagonistic Dickkopfs. Curr Biol 11(15):R592–R595. https://doi.org/10.1016/S0960-9822(01)00360-8

    Article  CAS  PubMed  Google Scholar 

  44. Rosi MC, Luccarini I, Grossi C, Fiorentini A, Spillantini MG, Prisco A, Scali C, Gianfriddo M, Caricasole A, Terstappen GC, Casamenti F (2010) Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem 112(6):1539–1551. https://doi.org/10.1111/j.1471-4159.2009.06566.x

    Article  CAS  PubMed  Google Scholar 

  45. Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F (2004) Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer’s brain. J Neurosci 24(26):6021–6027. https://doi.org/10.1523/JNEUROSCI.1381-04.2004

    Article  CAS  PubMed  Google Scholar 

  46. Glantschnig H, Hampton RA, Lu P, Zhao JZ, Vitelli S, Huang L, Haytko P, Cusick T, Ireland C, Jarantow SW, Ernst R, Wei N, Nantermet P, Scott KR, Fisher JE, Talamo F, Orsatti L, Reszka AA, Sandhu P, Kimmel D, Flores O, Strohl W, An Z, Wang F (2010) Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo. J Biol Chem 285(51):40135–40147. https://doi.org/10.1074/jbc.M110.166892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mpousis S, Thysiadis S, Avramidis N, Katsamakas S, Efthimiopoulos S, Sarli V (2016) Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer’s disease and related neurodegenerative tauopathies. Eur J Med Chem 108:28–38. https://doi.org/10.1016/j.ejmech.2015.11.024

    Article  CAS  PubMed  Google Scholar 

  48. Thysiadis S, Mpousis S, Avramidis N, Katsamakas S, Balomenos A, Remelli R, Efthimiopoulos S, Sarli V (2016) Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: synthesis, biological evaluation and structure-activity relationships. Bioorg Med Chem 24(5):1014–1022. https://doi.org/10.1016/j.bmc.2016.01.025

    Article  CAS  PubMed  Google Scholar 

  49. Cheng Z, Biechele T, Wei Z, Morrone S, Moon RT, Wang L, Xu W (2011) Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat Struct Mol Biol 18(11):1204–1210 http://www.nature.com/nsmb/journal/v18/n11/abs/nsmb.2139.html#supplementary-information

    Article  CAS  Google Scholar 

  50. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106):733–736. https://doi.org/10.1038/325733a0

    Article  CAS  PubMed  Google Scholar 

  51. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639. https://doi.org/10.1038/nature02621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Citron M, Teplow DB, Selkoe DJ (1995) Generation of amyloid β protein from its precursor is sequence specific. Neuron 14(3):661–670

    Article  CAS  Google Scholar 

  53. Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4(1):3. https://doi.org/10.1186/1756-6606-4-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gundersen E, Fan K, Haas K, Huryn D, Steven Jacobsen J, Kreft A, Martone R, Mayer S, Sonnenberg-Reines J, Sun SC, Zhou H (2005) Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors. Bioorg Med Chem Lett 15(7):1891–1894. https://doi.org/10.1016/j.bmcl.2005.02.006

    Article  CAS  PubMed  Google Scholar 

  55. Zhu YP, Xiao K, Yu HP, Ma LP, Xiong B, Zhang HY, Wang X, Li JY, Li J, Shen JK (2009) Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids. Acta Pharmacol Sin 30(2):259–269. https://doi.org/10.1038/aps.2008.26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Coburn CA, Stachel SJ, Li YM, Rush DM, Steele TG, Chen-Dodson E, Holloway MK, Xu M, Huang Q, Lai MT, DiMuzio J, Crouthamel MC, Shi XP, Sardana V, Chen Z, Munshi S, Kuo L, Makara GM, Annis DA, Tadikonda PK, Nash HM, Vacca JP, Wang T (2004) Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. J Med Chem 47(25):6117–6119. https://doi.org/10.1021/jm049388p

    Article  CAS  PubMed  Google Scholar 

  57. Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP (2004) Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem 47(26):6447–6450. https://doi.org/10.1021/jm049379g

    Article  CAS  PubMed  Google Scholar 

  58. Al-Tel TH, Semreen MH, Al-Qawasmeh RA, Schmidt MF, El-Awadi R, Ardah M, Zaarour R, Rao SN, El-Agnaf O (2011) Design, synthesis, and qualitative structure–activity evaluations of novel β-Secretase inhibitors as potential Alzheimer’s drug leads. J Med Chem 54(24):8373–8385

    Article  CAS  Google Scholar 

  59. Stachel SJ, Coburn CA, Steele TG, Crouthamel MC, Pietrak BL, Lai MT, Holloway MK, Munshi SK, Graham SL, Vacca JP (2006) Conformationally biased P3 amide replacements of beta-secretase inhibitors. Bioorg Med Chem Lett 16(3):641–644. https://doi.org/10.1016/j.bmcl.2005.10.032

    Article  CAS  PubMed  Google Scholar 

  60. Ajmani S, Janardhan S, Viswanadhan VN (2013) Toward a general predictive QSAR model for gamma-secretase inhibitors. Mol Divers 17(3):421–434. https://doi.org/10.1007/s11030-013-9441-2

    Article  CAS  PubMed  Google Scholar 

  61. Semighini EP (2015) In silico design of beta-secretase inhibitors in Alzheimer’s disease. Chem Biol Drug Des 86(3):284–290. https://doi.org/10.1111/cbdd.12492

    Article  CAS  PubMed  Google Scholar 

  62. Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Hawkins J, Hussain I, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S, Stemp G, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett 18(3):1017–1021. https://doi.org/10.1016/j.bmcl.2007.12.019

    Article  CAS  PubMed  Google Scholar 

  63. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, East P, Hawkins J, Howes C, Hussain I, Jeffrey P, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2008) Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability. J Med Chem 51(11):3313–3317. https://doi.org/10.1021/jm800138h

    Article  CAS  PubMed  Google Scholar 

  64. Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Second generation of BACE-1 inhibitors. Part 2: Optimisation of the non-prime side substituent. Bioorg Med Chem Lett 19(13):3669–3673. https://doi.org/10.1016/j.bmcl.2009.03.150

    Article  CAS  PubMed  Google Scholar 

  65. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. Bioorg Med Chem Lett 19(13):3664–3668. https://doi.org/10.1016/j.bmcl.2009.03.165

    Article  CAS  PubMed  Google Scholar 

  66. Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett 18(3):1022–1026. https://doi.org/10.1016/j.bmcl.2007.12.020

    Article  CAS  PubMed  Google Scholar 

  67. Edraki N, Firuzi O, Fatahi Y, Mahdavi M, Asadi M, Emami S, Divsalar K, Miri R, Iraji A, Khoshneviszadeh M (2015) N-(2-(Piperazin-1-yl) phenyl) arylamide derivatives as β-secretase (BACE1) inhibitors: simple synthesis by Ugi four-component reaction and biological evaluation. Arch Pharm 348(5):330–337

    Article  CAS  Google Scholar 

  68. Zeng H, Wu X (2016) Alzheimer’s disease drug development based on computer-aided drug design. Eur J Med Chem 121:851–863. https://doi.org/10.1016/j.ejmech.2015.08.039

    Article  CAS  PubMed  Google Scholar 

  69. Hernandez-Rodriguez M, Correa-Basurto J, Gutierrez A, Vitorica J, Rosales-Hernandez MC (2016) Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations. Eur J Med Chem 124:1142–1154. https://doi.org/10.1016/j.ejmech.2016.08.028

    Article  CAS  PubMed  Google Scholar 

  70. Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker EM, Strickland C, Voigt J (2008) Potent pyrrolidine- and piperidine-based BACE-1 inhibitors. Bioorg Med Chem Lett 18(1):414–417. https://doi.org/10.1016/j.bmcl.2007.10.116

    Article  CAS  PubMed  Google Scholar 

  71. Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B (2006) Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. J Mol Biol 355(2):249–261. https://doi.org/10.1016/j.jmb.2005.10.027

    Article  CAS  PubMed  Google Scholar 

  72. Lee AY, Gulnik SV, Erickson JW (1998) Conformational switching in an aspartic proteinase. Nat Struct Biol 5(10):866–871. https://doi.org/10.1038/2306

    Article  CAS  PubMed  Google Scholar 

  73. Tarazi H, Odeh RA, Al-Qawasmeh R, Yousef IA, Voelter W, Al-Tel TH (2017) Design, synthesis and SAR analysis of potent BACE1 inhibitors: possible lead drug candidates for Alzheimer’s disease. Eur J Med Chem 125:1213–1224. https://doi.org/10.1016/j.ejmech.2016.11.021

    Article  CAS  PubMed  Google Scholar 

  74. Coburn CA, Stachel SJ, Jones KG, Steele TG, Rush DM, DiMuzio J, Pietrak BL, Lai MT, Huang Q, Lineberger J, Jin L, Munshi S, Katharine Holloway M, Espeseth A, Simon A, Hazuda D, Graham SL, Vacca JP (2006) BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 16(14):3635–3638. https://doi.org/10.1016/j.bmcl.2006.04.076

    Article  CAS  PubMed  Google Scholar 

  75. Steele TG, Hills ID, Nomland AA, de Leon P, Allison T, McGaughey G, Colussi D, Tugusheva K, Haugabook SJ, Espeseth AS, Zuck P, Graham SL, Stachel SJ (2009) Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement. Bioorg Med Chem Lett 19(1):17–20. https://doi.org/10.1016/j.bmcl.2008.11.027

    Article  CAS  PubMed  Google Scholar 

  76. Prade E, Bittner HJ, Sarkar R, Lopez Del Amo JM, Althoff-Ospelt G, Multhaup G, Hildebrand PW, Reif B (2015) Structural mechanism of the interaction of Alzheimer disease Abeta fibrils with the non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide. J Biol Chem 290(48):28737–28745. https://doi.org/10.1074/jbc.M115.675215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Paravastu AK, Leapman RD, Yau WM, Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer’s beta-amyloid fibrils. Proc Natl Acad Sci U S A 105(47):18349–18354. https://doi.org/10.1073/pnas.0806270105

    Article  PubMed  PubMed Central  Google Scholar 

  78. de Almeida JP, Saldanha C (2010) Nonneuronal cholinergic system in human erythrocytes: biological role and clinical relevance. J Membr Biol 234(3):227–234. https://doi.org/10.1007/s00232-010-9250-9

    Article  CAS  PubMed  Google Scholar 

  79. Brimijoin S (1983) Molecular forms of acetylcholinesterase in brain, nerve and muscle: nature, localization and dynamics. Prog Neurobiol 21(4):291–322

    Article  CAS  Google Scholar 

  80. Heller M, Hanahan DJ (1972) Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim Biophys Acta 255(1):251–272

    Article  CAS  Google Scholar 

  81. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL (2010) Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 187(1–3):10–22. https://doi.org/10.1016/j.cbi.2010.01.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Silman I, Sussman JL (2008) Acetylcholinesterase: how is structure related to function? Chem Biol Interact 175(1–3):3–10

    Article  CAS  Google Scholar 

  83. Lane RM, Kivipelto M, Greig NH (2004) Acetylcholinesterase and its inhibition in Alzheimer disease. Clin Neuropharmacol 27(3):141–149

    Article  CAS  Google Scholar 

  84. Lane RM, Potkin SG, Enz A (2006) Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol 9(1):101–124. https://doi.org/10.1017/S1461145705005833

    Article  CAS  PubMed  Google Scholar 

  85. Recanatini M, Cavalli A, Hansch C (1997) A comparative QSAR analysis of acetylcholinesterase inhibitors currently studied for the treatment of Alzheimer’s disease. Chem Biol Interact 105(3):199–228. https://doi.org/10.1016/S0009-2797(97)00047-1

    Article  CAS  PubMed  Google Scholar 

  86. Sippl W, Contreras JM, Parrot I, Rival YM, Wermuth CG (2001) Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors. J Comput Aided Mol Des 15(5):395–410

    Article  CAS  Google Scholar 

  87. Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL (1993) Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A 90(19):9031–9035

    Article  CAS  Google Scholar 

  88. Ravelli RB, Raves ML, Ren Z, Bourgeois D, Roth M, Kroon J, Silman I, Sussman JL (1998) Static Laue diffraction studies on acetylcholinesterase. Acta Crystallogr D Biol Crystallogr 54(Pt 6 Pt 2):1359–1366. https://doi.org/10.1107/s0907444998005277

    Article  CAS  PubMed  Google Scholar 

  89. Raves ML, Harel M, Pang Y-P, Silman I, Kozikowski AP, Sussman JL (1997) Structure of acetylcholinesterase complexed with the nootropic alkaloid, (−)-huperzine A. Nat Struct Mol Biol 4(1):57–63. https://doi.org/10.1038/nsb0197-57

    Article  CAS  Google Scholar 

  90. Kosak U, Brus B, Knez D, Zakelj S, Trontelj J, Pislar A, Sink R, Jukic M, Zivin M, Podkowa A, Nachon F, Brazzolotto X, Stojan J, Kos J, Coquelle N, Salat K, Colletier JP, Gobec S (2017) The magic of crystal structure-based inhibitor optimization: development of a butyrylcholinesterase inhibitor with picomolar affinity and in vivo activity. J Med Chem. https://doi.org/10.1021/acs.jmedchem.7b01086

    Article  Google Scholar 

  91. da Silva CH, Campo VL, Carvalho I, Taft CA (2006) Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer’s disease. J Mol Graph Model 25(2):169–175. https://doi.org/10.1016/j.jmgm.2005.12.002

    Article  CAS  PubMed  Google Scholar 

  92. Kryger G, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with E2020 (Aricept (R)): implications for the design of new anti-Alzheimer drugs. Structure 7(3):297–307. https://doi.org/10.1016/S0969-2126(99)80040-9

    Article  CAS  PubMed  Google Scholar 

  93. Alcaro S, Arcone R, Vecchio I, Ortuso F, Gallelli A, Pasceri R, Procopio A, Iannone M (2007) Molecular modelling and enzymatic studies of acetylcholinesterase and butyrylcholinesterase recognition with paraquat and related compounds. SAR QSAR Environ Res 18(5–6):595–602. https://doi.org/10.1080/10629360701428433

    Article  CAS  PubMed  Google Scholar 

  94. da Silva CH, Carvalho I, Taft CA (2007) Virtual screening, molecular interaction field, molecular dynamics, docking, density functional, and ADMET properties of novel AChE inhibitors in Alzheimer’s disease. J Biomol Struct Dyn 24(6):515–524. https://doi.org/10.1080/07391102.2007.10507140

    Article  PubMed  Google Scholar 

  95. Fang L, Appenroth D, Decker M, Kiehntopf M, Lupp A, Peng SX, Fleck C, Zhang YH, Lehmann JC (2008) NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity. J Med Chem 51(24):7666–7669. https://doi.org/10.1021/jm801131a

    Article  CAS  PubMed  Google Scholar 

  96. Rydberg EH, Brumshtein B, Greenblatt HM, Wong DM, Shaya D, Williams LD, Carlier PR, Pang YP, Silman I, Sussman JL (2006) Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J Med Chem 49(18):5491–5500. https://doi.org/10.1021/jm060164b

    Article  CAS  PubMed  Google Scholar 

  97. Badran MM, Abdel Hakeem M, Abuel-Maaty SM, El-Malah A, Abdel Salam RM (2010) Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer’s disease. Arch Pharm (Weinheim) 343(10):590–601. https://doi.org/10.1002/ardp.200900226

    Article  CAS  Google Scholar 

  98. Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z (2012) Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem 60(24):6131–6138. https://doi.org/10.1021/jf300589c

    Article  CAS  PubMed  Google Scholar 

  99. El-Malah A, Gedawy EM, Kassab AE, Salam RMA (2014) Novel tacrine analogs as potential cholinesterase inhibitors in Alzheimer’s disease. Arch Pharm 347(2):96–103

    Article  CAS  Google Scholar 

  100. Nicolet Y, Lockridge O, Masson P, Fontecilla-Camps JC, Nachon F (2003) Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J Biol Chem 278(42):41141–41147. https://doi.org/10.1074/jbc.M210241200

    Article  CAS  PubMed  Google Scholar 

  101. Arab S, Sadat-Ebrahimi SE, Mohammadi-Khanaposhtani M, Moradi A, Nadri H, Mahdavi M, Moghimi S, Asadi M, Firoozpour L, Pirali-Hamedani M, Shafiee A, Foroumadi A (2015) Synthesis and evaluation of chroman-4-one linked to N-benzyl pyridinium derivatives as new acetylcholinesterase inhibitors. Arch Pharm 348(9):643–649. https://doi.org/10.1002/ardp.201500149

    Article  CAS  Google Scholar 

  102. Liu Z, Fang L, Zhang H, Gou S, Chen L (2017) Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property. Bioorg Med Chem 25(8):2387–2398. https://doi.org/10.1016/j.bmc.2017.02.049

    Article  CAS  PubMed  Google Scholar 

  103. Nachon F, Carletti E, Ronco C, Trovaslet M, Nicolet Y, Jean L, Renard PY (2013) Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase. Biochem J 453(3):393–399. https://doi.org/10.1042/BJ20130013

    Article  CAS  PubMed  Google Scholar 

  104. Mehrabi F, Pourshojaei Y, Moradi A, Sharifzadeh M, Khosravani L, Sabourian R, Rahmani-Nezhad S, Mohammadi-Khanaposhtani M, Mahdavi M, Asadipour A, Rahimi HR, Moghimi S, Foroumadi A (2017) Design, synthesis, molecular modeling and anticholinesterase activity of benzylidene-benzofuran-3-ones containing cyclic amine side chain. Future Med Chem 9(7):659–671. https://doi.org/10.4155/fmc-2016-0237

    Article  CAS  PubMed  Google Scholar 

  105. da Silva Goncalves A, Franca TC, Vital de Oliveira O (2016) Computational studies of acetylcholinesterase complexed with fullerene derivatives: a new insight for Alzheimer disease treatment. J Biomol Struct Dyn 34(6):1307–1316. https://doi.org/10.1080/07391102.2015.1077345

    Article  CAS  PubMed  Google Scholar 

  106. Carletti E, Colletier JP, Dupeux F, Trovaslet M, Masson P, Nachon F (2010) Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation. J Med Chem 53(10):4002–4008. https://doi.org/10.1021/jm901853b

    Article  CAS  PubMed  Google Scholar 

  107. Basiri A, Xiao M, McCarthy A, Dutta D, Byrareddy SN, Conda-Sheridan M (2017) Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors. Bioorg Med Chem Lett 27(2):228–231. https://doi.org/10.1016/j.bmcl.2016.11.065

    Article  CAS  PubMed  Google Scholar 

  108. Yu Q, Holloway HW, Flippen-Anderson JL, Hoffman B, Brossi A, Greig NH (2001) Methyl analogues of the experimental Alzheimer drug phenserine: synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action. J Med Chem 44(24):4062–4071

    Article  CAS  Google Scholar 

  109. Camps P, Formosa X, Galdeano C, Munoz-Torrero D, Ramírez L, Gómez E, Isambert N, Lavilla R, Badia A, Clos MV (2009) Pyrano [3, 2-c] quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase-and β-amyloid-directed anti-Alzheimer compounds. J Med Chem 52(17):5365–5379

    Article  CAS  Google Scholar 

  110. Bourne Y, Kolb HC, Radic Z, Sharpless KB, Taylor P, Marchot P (2004) Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation. Proc Natl Acad Sci U S A 101(6):1449–1454. https://doi.org/10.1073/pnas.0308206100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL (2005) Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase. J Am Chem Soc 127(31):11029–11036. https://doi.org/10.1021/ja051765f

    Article  CAS  PubMed  Google Scholar 

  112. Ul-Haq Z, Khan W, Kalsoom S, Ansari FL (2010) In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of beta-amyloid plaques associated with Alzheimer’s disease. Theor Biol Med Model 7(1):22. https://doi.org/10.1186/1742-4682-7-22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hamulakova S, Janovec L, Hrabinova M, Kristian P, Kuca K, Banasova M, Imrich J (2012) Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer’s disease. Eur J Med Chem 55:23–31. https://doi.org/10.1016/j.ejmech.2012.06.051

    Article  CAS  PubMed  Google Scholar 

  114. Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Shafferman A, Silman I, Sussman JL (2000) Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr D Biol Crystallogr 56(Pt 11):1385–1394. https://doi.org/10.1107/S0907444900010659

    Article  CAS  PubMed  Google Scholar 

  115. Makhaeva GF, Radchenko EV, Baskin II, Palyulin VA, Richardson RJ, Zefirov NS (2012) Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer’s disease. SAR QSAR Environ Res 23(7–8):627–647. https://doi.org/10.1080/1062936X.2012.679690

    Article  CAS  PubMed  Google Scholar 

  116. Bourne Y, Radic Z, Sulzenbacher G, Kim E, Taylor P, Marchot P (2006) Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding. J Biol Chem 281(39):29256–29267. https://doi.org/10.1074/jbc.M603018200

    Article  CAS  PubMed  Google Scholar 

  117. Ozturan Ozer E, Tan OU, Ozadali K, Kucukkilinc T, Balkan A, Ucar G (2013) Synthesis, molecular modeling and evaluation of novel N′-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Abeta aggregation. Bioorg Med Chem Lett 23(2):440–443. https://doi.org/10.1016/j.bmcl.2012.11.064

    Article  CAS  PubMed  Google Scholar 

  118. Geldmacher DS (2004) Donepezil (Aricept®) for treatment of Alzheimer’s disease and other dementing conditions. Expert Rev Neurother 4(1):5–16

    Article  CAS  Google Scholar 

  119. Maggi N, Pasqualucci CR, Ballotta R, Sensi P (1966) Rifampicin: a new orally active rifamycin. Chemotherapy 11(5):285–292. https://doi.org/10.1159/000220462

    Article  CAS  PubMed  Google Scholar 

  120. Li RS, Wang XB, Hu XJ, Kong LY (2013) Design, synthesis and evaluation of flavonoid derivatives as potential multifunctional acetylcholinesterase inhibitors against Alzheimer’s disease. Bioorg Med Chem Lett 23(9):2636–2641. https://doi.org/10.1016/j.bmcl.2013.02.095

    Article  CAS  PubMed  Google Scholar 

  121. Luo W, Su YB, Hong C, Tian RG, Su LP, Wang YQ, Li Y, Yue JJ, Wang CJ (2013) Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents. Bioorg Med Chem 21(23):7275–7282. https://doi.org/10.1016/j.bmc.2013.09.061

    Article  CAS  PubMed  Google Scholar 

  122. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt F (2000) Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev (4):CD001191

    Google Scholar 

  123. Xie SS, Wang XB, Li JY, Yang L, Kong LY (2013) Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur J Med Chem 64:540–553. https://doi.org/10.1016/j.ejmech.2013.03.051

    Article  CAS  PubMed  Google Scholar 

  124. Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M, Boonyarat C (2014) Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 75:21–30. https://doi.org/10.1016/j.ejmech.2014.01.020

    Article  CAS  PubMed  Google Scholar 

  125. Colletier JP, Sanson B, Nachon F, Gabellieri E, Fattorusso C, Campiani G, Weik M (2006) Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor. J Am Chem Soc 128(14):4526–4527. https://doi.org/10.1021/ja058683b

    Article  CAS  PubMed  Google Scholar 

  126. Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y (2014) Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 76:314–331. https://doi.org/10.1016/j.ejmech.2014.02.045

    Article  CAS  PubMed  Google Scholar 

  127. Pudlo M, Luzet V, Ismaili L, Tomassoli I, Iutzeler A, Refouvelet B (2014) Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease. Bioorg Med Chem 22(8):2496–2507. https://doi.org/10.1016/j.bmc.2014.02.046

    Article  CAS  PubMed  Google Scholar 

  128. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ (2012) Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 55(22):10282–10286. https://doi.org/10.1021/jm300871x

    Article  CAS  PubMed  Google Scholar 

  129. Hong C, Luo W, Yao D, Su YB, Zhang X, Tian RG, Wang CJ (2014) Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase. Bioorg Med Chem 22(12):3213–3219. https://doi.org/10.1016/j.bmc.2014.03.045

    Article  CAS  PubMed  Google Scholar 

  130. Lan JS, Xie SS, Li SY, Pan LF, Wang XB, Kong LY (2014) Design, synthesis and evaluation of novel tacrine-(beta-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 22(21):6089–6104. https://doi.org/10.1016/j.bmc.2014.08.035

    Article  CAS  PubMed  Google Scholar 

  131. Li S-Y, Jiang N, Xie S-S, Wang KD, Wang X-B, Kong L-Y (2014) Design, synthesis and evaluation of novel tacrine–rhein hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Org Biomol Chem 12(5):801–814

    Article  CAS  Google Scholar 

  132. Stoddard SV, Hamann MT, Wadkins RM (2014) Insights and ideas garnered from marine metabolites for development of dual-function acetylcholinesterase and amyloid-beta aggregation inhibitors. Mar Drugs 12(4):2114–2131. https://doi.org/10.3390/md12042114

    Article  PubMed  PubMed Central  Google Scholar 

  133. Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with (−)-galanthamine at 2.3 Å resolution. FEBS Lett 463(3):321–326. https://doi.org/10.1016/s0014-5793(99)01637-3

    Article  CAS  PubMed  Google Scholar 

  134. Bautista-Aguilera OM, Esteban G, Bolea I, Nikolic K, Agbaba D, Moraleda I, Iriepa I, Samadi A, Soriano E, Unzeta M, Marco-Contelles J (2014) Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 75:82–95. https://doi.org/10.1016/j.ejmech.2013.12.028

    Article  CAS  PubMed  Google Scholar 

  135. Bourne Y, Grassi J, Bougis PE, Marchot P (1999) Conformational flexibility of the acetylcholinesterase tetramer suggested by X-ray crystallography. J Biol Chem 274(43):30370–30376. https://doi.org/10.1074/jbc.274.43.30370

    Article  CAS  PubMed  Google Scholar 

  136. Ngamelue MN, Homma K, Lockridge O, Asojo OA (2007) Crystallization and X-ray structure of full-length recombinant human butyrylcholinesterase. Acta Crystallogr Sect F Struct Biol Cryst Commun 63(Pt 9):723–727. https://doi.org/10.1107/S1744309107037335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T (2008) Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A 105(15):5739–5744. https://doi.org/10.1073/pnas.0710626105

    Article  PubMed  PubMed Central  Google Scholar 

  138. Binda C, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi A (2007) Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem 50(23):5848–5852. https://doi.org/10.1021/jm070677y

    Article  CAS  Google Scholar 

  139. Bautista-Aguilera OM, Esteban G, Chioua M, Nikolic K, Agbaba D, Moraleda I, Iriepa I, Soriano E, Samadi A, Unzeta M, Marco-Contelles J (2014) Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. Drug Des Devel Ther 8:1893–1910. https://doi.org/10.2147/DDDT.S69258

    Article  PubMed  PubMed Central  Google Scholar 

  140. Goyal M, Dhanjal JK, Goyal S, Tyagi C, Hamid R, Grover A (2014) Development of dual inhibitors against Alzheimer’s disease using fragment-based QSAR and molecular docking. Biomed Res Int 2014:979606. https://doi.org/10.1155/2014/979606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cheung J, Gary EN, Shiomi K, Rosenberry TL (2013) Structures of human acetylcholinesterase bound to dihydrotanshinone I and territrem B show peripheral site flexibility. ACS Med Chem Lett 4(11):1091–1096. https://doi.org/10.1021/ml400304w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Xie SS, Wang X, Jiang N, Yu W, Wang KD, Lan JS, Li ZR, Kong LY (2015) Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur J Med Chem 95:153–165. https://doi.org/10.1016/j.ejmech.2015.03.040

    Article  CAS  PubMed  Google Scholar 

  143. Xie SS, Lan JS, Wang XB, Jiang N, Dong G, Li ZR, Wang KD, Guo PP, Kong LY (2015) Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer’s disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties. Eur J Med Chem 93:42–50. https://doi.org/10.1016/j.ejmech.2015.01.058

    Article  CAS  PubMed  Google Scholar 

  144. Luo XT, Wang CM, Liu Y, Huang ZG (2015) New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur J Med Chem 103:302–311. https://doi.org/10.1016/j.ejmech.2015.08.052

    Article  CAS  PubMed  Google Scholar 

  145. Sang Z, Qiang X, Li Y, Yuan W, Liu Q, Shi Y, Ang W, Luo Y, Tan Z, Deng Y (2015) Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 94:348–366. https://doi.org/10.1016/j.ejmech.2015.02.063

    Article  CAS  PubMed  Google Scholar 

  146. Liu Q, Qiang X, Li Y, Sang Z, Tan Z, Deng Y (2015) Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 23(5):911–923. https://doi.org/10.1016/j.bmc.2015.01.042

    Article  CAS  PubMed  Google Scholar 

  147. Bajda M, Jonczyk J, Malawska B, Czarnecka K, Girek M, Olszewska P, Sikora J, Mikiciuk-Olasik E, Skibinski R, Gumieniczek A, Szymanski P (2015) Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 23(17):5610–5618. https://doi.org/10.1016/j.bmc.2015.07.029

    Article  CAS  PubMed  Google Scholar 

  148. Benchekroun M, Bartolini M, Egea J, Romero A, Soriano E, Pudlo M, Luzet V, Andrisano V, Jimeno ML, Lopez MG, Wehle S, Gharbi T, Refouvelet B, de Andres L, Herrera-Arozamena C, Monti B, Bolognesi ML, Rodriguez-Franco MI, Decker M, Marco-Contelles J, Ismaili L (2015) Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids. ChemMedChem 10(3):523–539. https://doi.org/10.1002/cmdc.201402409

    Article  CAS  PubMed  Google Scholar 

  149. Dominguez JL, Fernandez-Nieto F, Castro M, Catto M, Paleo MR, Porto S, Sardina FJ, Brea JM, Carotti A, Villaverde MC, Sussman F (2015) Computer-aided structure-based design of multitarget leads for Alzheimer’s disease. J Chem Inf Model 55(1):135–148. https://doi.org/10.1021/ci500555g

    Article  CAS  PubMed  Google Scholar 

  150. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290(5489):150–153. https://doi.org/10.1126/science.290.5489.150

    Article  CAS  PubMed  Google Scholar 

  151. Wu MY, Esteban G, Brogi S, Shionoya M, Wang L, Campiani G, Unzeta M, Inokuchi T, Butini S, Marco-Contelles J (2016) Donepezil-like multifunctional agents: design, synthesis, molecular modeling and biological evaluation. Eur J Med Chem 121:864–879. https://doi.org/10.1016/j.ejmech.2015.10.001

    Article  CAS  PubMed  Google Scholar 

  152. Najafi Z, Saeedi M, Mahdavi M, Sabourian R, Khanavi M, Tehrani MB, Moghadam FH, Edraki N, Karimpor-Razkenari E, Sharifzadeh M, Foroumadi A, Shafiee A, Akbarzadeh T (2016) Design and synthesis of novel anti-Alzheimer’s agents: Acridine-chromenone and quinoline-chromenone hybrids. Bioorg Chem 67:84–94. https://doi.org/10.1016/j.bioorg.2016.06.001

    Article  CAS  PubMed  Google Scholar 

  153. Zhang C, Du QY, Chen LD, Wu WH, Liao SY, Yu LH, Liang XT (2016) Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease. Eur J Med Chem 116:200–209. https://doi.org/10.1016/j.ejmech.2016.03.077

    Article  CAS  PubMed  Google Scholar 

  154. Luo W, Wang T, Hong C, Yang YC, Chen Y, Cen J, Xie SQ, Wang CJ (2016) Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents. Eur J Med Chem 122:17–26. https://doi.org/10.1016/j.ejmech.2016.06.022

    Article  CAS  PubMed  Google Scholar 

  155. Luo W, Chen Y, Wang T, Hong C, Chang LP, Chang CC, Yang YC, Xie SQ, Wang CJ (2016) Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities. Bioorg Med Chem 24(4):672–680. https://doi.org/10.1016/j.bmc.2015.12.031

    Article  CAS  PubMed  Google Scholar 

  156. Wang ZM, Cai P, Liu QH, Xu DQ, Yang XL, Wu JJ, Kong LY, Wang XB (2016) Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur J Med Chem 123:282–297. https://doi.org/10.1016/j.ejmech.2016.07.052

    Article  CAS  PubMed  Google Scholar 

  157. Knez D, Brus B, Coquelle N, Sosic I, Sink R, Brazzolotto X, Mravljak J, Colletier JP, Gobec S (2015) Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents. Bioorg Med Chem 23(15):4442–4452. https://doi.org/10.1016/j.bmc.2015.06.010

    Article  CAS  PubMed  Google Scholar 

  158. Xie SS, Lan JS, Wang X, Wang ZM, Jiang N, Li F, Wu JJ, Wang J, Kong LY (2016) Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 24(7):1528–1539. https://doi.org/10.1016/j.bmc.2016.02.023

    Article  CAS  PubMed  Google Scholar 

  159. Koca M, Yerdelen KO, Anil B, Kasap Z, Sevindik H, Ozyurek I, Gunesacar G, Turkaydin K (2016) Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents. J Enzyme Inhib Med Chem 31(sup2):13–23

    Article  CAS  Google Scholar 

  160. Wang Y, Sun Y, Guo Y, Wang Z, Huang L, Li X (2016) Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J Enzyme Inhib Med Chem 31(3):389–397. https://doi.org/10.3109/14756366.2015.1024675

    Article  CAS  PubMed  Google Scholar 

  161. Mohamed T, Rao PPN (2017) 2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: development and structure-activity relationship (SAR) studies. Eur J Med Chem 126:823–843. https://doi.org/10.1016/j.ejmech.2016.12.005

    Article  CAS  PubMed  Google Scholar 

  162. Panek D, Wieckowska A, Wichur T, Bajda M, Godyn J, Jonczyk J, Mika K, Janockova J, Soukup O, Knez D, Korabecny J, Gobec S, Malawska B (2017) Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation. Eur J Med Chem 125:676–695. https://doi.org/10.1016/j.ejmech.2016.09.078

    Article  CAS  PubMed  Google Scholar 

  163. Rueeger H, Lueoend R, Rogel O, Rondeau JM, Mobitz H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S, Neumann U (2012) Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid beta-peptides. J Med Chem 55(7):3364–3386. https://doi.org/10.1021/jm300069y

    Article  CAS  PubMed  Google Scholar 

  164. Najafi Z, Mahdavi M, Saeedi M, Karimpour-Razkenari E, Asatouri R, Vafadarnejad F, Moghadam FH, Khanavi M, Sharifzadeh M, Akbarzadeh T (2017) Novel tacrine-1,2,3-triazole hybrids: in vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors. Eur J Med Chem 125:1200–1212. https://doi.org/10.1016/j.ejmech.2016.11.008

    Article  CAS  PubMed  Google Scholar 

  165. Sang Z, Qiang X, Li Y, Xu R, Cao Z, Song Q, Wang T, Zhang X, Liu H, Tan Z, Deng Y (2017) Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 135:307–323. https://doi.org/10.1016/j.ejmech.2017.04.054

    Article  CAS  PubMed  Google Scholar 

  166. Jameel E, Meena P, Maqbool M, Kumar J, Ahmed W, Mumtazuddin S, Tiwari M, Hoda N, Jayaram B (2017) Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents. Eur J Med Chem 136:36–51. https://doi.org/10.1016/j.ejmech.2017.04.064

    Article  CAS  PubMed  Google Scholar 

  167. Sang Z, Pan W, Wang K, Ma Q, Yu L, Liu W (2017) Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem 25(12):3006–3017. https://doi.org/10.1016/j.bmc.2017.03.070

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Sotirios Katsamakas and Dimitra Hadjipavlou-Litina contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Sotirios Katsamakas & Dimitra Hadjipavlou-Litina

Authors
  1. Sotirios Katsamakas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitra Hadjipavlou-Litina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dimitra Hadjipavlou-Litina .

Editor information

Editors and Affiliations

  1. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India

    Kunal Roy

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Katsamakas, S., Hadjipavlou-Litina, D. (2018). Computational Design of Multitarget Drugs Against Alzheimer’s Disease. In: Roy, K. (eds) Multi-Target Drug Design Using Chem-Bioinformatic Approaches. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/7653_2018_25

Download citation

  • DOI: https://doi.org/10.1007/7653_2018_25

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8732-0

  • Online ISBN: 978-1-4939-8733-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation