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Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors

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Abstract

Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure–activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds (\( {\text{r}}^{ 2}_{ 6 8} = 0. 9 4 \), F-statistic = 125.8, \( {\text{r}}^{ 2}_{\text{LOO}} { = 0} . 9 2 \), \( {\text{r}}^{ 2}_{\text{PRESS}} \) against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 μM.

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References

  1. Clark CM, Karlawish JH (2003) Ann Intern Med 138(5):400–410

    Article  Google Scholar 

  2. Chen S, Zhang X-J, Li L, Le W-D (2007) Curr Neuropharmacol 5(2):127–134

    Article  CAS  Google Scholar 

  3. Terry AV (2003) J Pharmacol Exp Ther 306(3):821–827

    Article  CAS  Google Scholar 

  4. Bachurin SO (2003) Med Res Rev 23(1):48–88

    Article  CAS  Google Scholar 

  5. Rollinger JM, Hornick A, Langer T, Stuppner H, Prast H (2004) J Med Chem 47(25):6248–6254

    Article  CAS  Google Scholar 

  6. Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH (2003) Ann Neurol 54(2):235–238

    Article  CAS  Google Scholar 

  7. Mukherjee PK, Satheeshkumar N, Venkatesh P, Venkatesh M (2011) Mini Rev Med Chem 11(3):247–262

    Article  CAS  Google Scholar 

  8. Lu SH, Wu JW, Liu HL, Zhao JH, Liu KT, Chuang CK, Lin HY, Tsai WB, Ho Y (2011) J Biomed Sci 18:8–18

    Article  CAS  Google Scholar 

  9. Whittaker VP (1990) Trends Pharmacol Sci 11(1):8–13

    Article  CAS  Google Scholar 

  10. Purves D, George A, David F, William H, Anthony L, James M, Leonard W (2008) Neuroscience, 4th edn. Sinauer Associates Inc, Sunderland MA, pp 121–122

    Google Scholar 

  11. Quinn DM (1987) Chem Rev 87(5):955–979

    Article  CAS  Google Scholar 

  12. Taylor P, Radic Z (1994) Annu Rev Pharmacol Toxicol 34:281–320

    Article  CAS  Google Scholar 

  13. Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I (1991) Science 253(5022):872–879

    Article  CAS  Google Scholar 

  14. Sussman JL, Harel M, Silman I (1993) Chem Biol Interact 87(1–3):187–197

    Article  CAS  Google Scholar 

  15. Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL (1993) PNAS 90(19):9031–9035

    Article  CAS  Google Scholar 

  16. Silman I, Harel M, Axelsen P, Raves M, Sussman JL (1994) Biochem Soc Trans 22(3):745–749

    CAS  Google Scholar 

  17. Harel M, Silman I, Quinn DM, Nair HK, Sussman JL (1996) J Am Chem Soc 118(10):2340–2346

    Article  CAS  Google Scholar 

  18. Greenblatt HMKG, Lewis T, Silman I, Sussman JL (1999) FEBS Lett 463:321–326

    Article  CAS  Google Scholar 

  19. Kryger G, Silman I, Sussman JL (1998) J Physiol 92(3–4):191–194

    CAS  Google Scholar 

  20. Inestrosa NC, Dinamarca MC, Alvarez A (2008) FEBS J 275(4):625–632

    Article  CAS  Google Scholar 

  21. Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S (2003) Neurobiol Aging 24(6):777–787

    Article  CAS  Google Scholar 

  22. Rees TM, Berson A, Sklan EH, Younkin L, Younkin S, Brimijoin S, Soreq H (2005) Curr Alzheimer Res 2(3):291–300

    Article  CAS  Google Scholar 

  23. De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman I, Inestrosa NC (2001) Biochemistry 40(35):10447–10457

    Article  Google Scholar 

  24. National Pesticide Information Center-Diazinon Technical Fact Sheet (2012). http://npic.orst.edu/factsheets/diazinontech.pdf

  25. Stoelting RK (1999) Anticholinesterase drugs and cholinergic agonists in pharmacology and physiology in anesthetic practice. Lippincott-Raven, Philadelphia

    Google Scholar 

  26. Taylor P, Hardman JG, Limbird LE, Molinoff PB., Ruddon RW, Gilman AG (1996) Autonomic pharmacology: cholinergic drugs the pharmacologial basis of therapeutics. The McGraw-Hill Companies, Columbus, Ohio

  27. Taha MO, Bustanji Y, Al-Ghussein MAS, Mohammad M, Zalloum H, Al-Masri IM, Atallah N (2008) J Med Chem 51:2062–2077

    Article  CAS  Google Scholar 

  28. CATALYST 4.11 Users’ Manual (2005) Accelrys Software Inc San Diego CA

  29. Taha MO, Atallah N, Al-Bakri AG, Paradis-Bleau C, Zalloum H, Younis KS, Levesque RC (2008) Bioorg Med Chem 16(3):1218–1235

    Article  CAS  Google Scholar 

  30. Taha MO, Bustanji Y, Al-Bakri AG, Yousef A-M, Zalloum WA, Al-Masri IM, Atallah N (2007) J Mol Graph Model 25(6):870–884

    Article  CAS  Google Scholar 

  31. Al-masri IM, Mohammad MK, Taha MO (2008) ChemMedChem 3(11):1763–1779

    Article  CAS  Google Scholar 

  32. Taha MO, Dahbiyeh LA, Bustanji Y, Zalloum H, Saleh S (2008) J Med Chem 51:6478–6494

    Article  CAS  Google Scholar 

  33. Al-Nadaf AS, Taha MO (2010) Bioorg Med Chem 18:3088–3115

    Article  CAS  Google Scholar 

  34. Abu-Hammad AM, Taha MO (2009) J Chem Inf Model 49:978–996

    Article  CAS  Google Scholar 

  35. Abu Khalaf R, Abu Sheikha G, Bustanji Y, Taha MO (2010) Eur J Med Chem 45(4):1598–1617

    Article  CAS  Google Scholar 

  36. Al-Sha’er MA, Taha MO (2010) Eur J Med Chem 45(9):4316–4330

    Article  Google Scholar 

  37. Al-Sha’er MA, Taha MO (2010) J Chem Inf Model 50(9):1706–1723

    Article  Google Scholar 

  38. Habash M, Taha MO (2011) Bioorg Med Chem 19(16):4746–4771

    Article  CAS  Google Scholar 

  39. Shahin R, Alqtaishat S, Taha MO (2012) J Comput Aided Mol Des 26(2):249–266

    Article  CAS  Google Scholar 

  40. Suaifan GARY, Shehadehh M, Al-Ijel H, Taha MO (2012) J Mol Graph Model 37:1–26

    Article  CAS  Google Scholar 

  41. Shahin R, Taha MO (2012) Bioorg Med Chem 20(1):377–400

    Article  CAS  Google Scholar 

  42. Taha MO, Qandil AM, Al-Haraznah T, Khalaf RA, Zalloum H, Al-Bakri AG (2011) Chem Biol Drug Des 78(3):391–407

    Article  CAS  Google Scholar 

  43. Al-Nadaf AH, Taha MO (2011) J Mol Graph Model 29(6):843–864

    Article  CAS  Google Scholar 

  44. Al-Najjar BO, Wahab HA, Tengku Muhammad TS, Shu-Chien AC, Ahmad Noruddin NA, Taha MO (2011) Eur J Med Chem 46(6):2513–2529

    Article  CAS  Google Scholar 

  45. CERIUS2, QSAR Users’ Manual, version 4.10, Accelrys Inc., San Diego, CA (2005) 43–88, 221–235, 237–250

  46. Discovery Studio 2.5.5 User Guide (2010) Accelrys Inc., San Diego

  47. CS ChemDraw Ultra 6.0, Cambridge Soft Corp., USA

  48. Fang L, Kraus B, Lehmann J, Heilmann J, Zhang Y, Decker M (2008) Bioorg Med Chem Lett 18(9):2905–2909

    Article  CAS  Google Scholar 

  49. Fang L, Decker M, Roegler C, Lehmann J, Appenroth D, Fleck C, Kiehntopf M, Deufel T, Peng S, Zhang Y (2008) J Med Chem 51(4):713–716

    Article  CAS  Google Scholar 

  50. Fang L, Zhang Y, Decker M, Appenroth D, Fleck C, Jumpertz S, Mohr K, Trankle C (2010) J Med Chem 53(5):2094–2103

    Article  CAS  Google Scholar 

  51. Rook Y, Schmidtke K-U, Gaube F, Schepmann D, Wünsch B, Heilmann J, Lehmann J, Winckler T (2010) J Med Chem 53(9):3611–3617

    Article  CAS  Google Scholar 

  52. Schott Y, Decker M, Rommelspacher H, Lehmann J (2006) Bioorg Med Chem Lett 16(22):5840–5843

    Article  CAS  Google Scholar 

  53. Decker M, Krauth F, Lehmann J (2006) Bioorg Med Chem 14(6):1966–1977

    Article  CAS  Google Scholar 

  54. Decker M, Kraus B, Heilmann J (2008) Bioorg Med Chem 16(8):4252–4261

    Article  CAS  Google Scholar 

  55. Decker M (2006) J Med Chem 49(18):5411–5413

    Article  CAS  Google Scholar 

  56. Sutter J, Guner O, Hoffmann R, Li H, Waldman M (2000). In: Guner OF (ed) Pharmacophore perception, development,and use in drug design. International University Line, La Jolla, pp 501–511

  57. Kurogi Y, Güner OF (2001) Curr Med Chem 8(9):1035–1055

    Article  CAS  Google Scholar 

  58. Poptodorov K, Luu T, Langer T, Hoffmann R (2006). In: Hoffmann RD (ed) Methods and principles in medicinal chemistry: pharmacophores and pharmacophores searches, vol 2. Wiley-VCH Weinheim, pp 17–47

  59. Li H, Sutter J, Hoffmann R (2000) Pharmacophore perception development and use in drug design ed. International University Line, La Jolla, CA, pp 173–178

    Google Scholar 

  60. Bersuker I, Bahçeci S, Boggs J (2000) Pharmacophore perception development and use in drug design. International University Line, La Jolla, pp 457–473

    Google Scholar 

  61. Fischer R (1966) The principle of experimentation illustrated by a psycho-physical. ExpeHafner Publishing Co, 8th ed. Hafner Publishing,New York Chapter II

  62. Krovat EM, Langer T (2003) J Med Chem 46(5):716–726

    Article  CAS  Google Scholar 

  63. Triballeau N, Acher F, Brabet I, Pin JP, Bertrand HO (2005) J Med Chem 48(7):2534–2547

    Article  CAS  Google Scholar 

  64. Verdonk ML, Berdini V, Hartshorn MJ, Mooij WT, Murray CW, Taylor RD, Watson P (2004). J Chem Inf Comput Sci 44(3)

  65. Kirchmair J, Markt P, Distinto S, Wolber G, Langer T (2008). J Comput Aided Mol Des 22(3–4)

    Google Scholar 

  66. Irwin JJ, Shoichet BK (2005) J Chem Inf Model 45(1):177–182

    Article  CAS  Google Scholar 

  67. Jacobsson M, Lidén P, Stjernschantz E, Boström H, Norinder U (2003) J Med Chem 46(26):5781–5789

    Article  CAS  Google Scholar 

  68. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Adv Drug Deliv Rev 46(1–3):1–3

    Google Scholar 

  69. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) J Med Chem 45(12):2615–2623

    Article  CAS  Google Scholar 

  70. Ellman G, Courtney K, Andresjr V, Featherstone R (1961) Biochem Pharmacol 7(2):88–95

    Article  CAS  Google Scholar 

  71. Venkatachalam CM, Jiang X, Oldfield T, Waldman M (2003) J Mol Graph Model 21(4):289–307

    Article  CAS  Google Scholar 

  72. Tamura M, Nakao H, Yoshizaki H, Shiratsuchi M, Shigyo H, Yamada H, Ozawa T, Totsuka J, Hidaka H (2005) Biochim Biophys Acta 1754(1–2):1–2

    Google Scholar 

  73. Bemis GW, Murcko MA (1996) J Med Chem 39(15):2887–2893

    Article  CAS  Google Scholar 

  74. Poornima CS, Dean PM (1995) J Comput Aided Mol Des 9:500–512

    Article  CAS  Google Scholar 

  75. Poornima CS, Dean PM (1995) J Comput Aided Mol Des 9:513–520

    Article  CAS  Google Scholar 

  76. Poornima CS, Dean PM (1995) J Comput Aided Mol Des 9:521–531

    Article  CAS  Google Scholar 

  77. Rogers D, Hopfinger AJ (1994) J Chem Inf Comput Sci 34(4):854–866

    Article  CAS  Google Scholar 

  78. Walters W, Namchuk M (2003) Nat Rev Drug Discov 2:259–266

    Article  CAS  Google Scholar 

  79. Brian KS (2006) J Med Chem 49:7274–7277

    Article  Google Scholar 

  80. Hasegawa K, Miyashita Y, Funatsu KJ (1997) Chem Inf Comput Sci 37(2):306–310

    CAS  Google Scholar 

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Acknowledgments

This project was sponsored by the Deanship of Scientific Research at the University of Jordan. The authors wish to thank the National Cancer Institute for freely providing hit compounds for experimental validation.

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Authors and Affiliations

  1. Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan

    Sawsan Abuhamdah

  2. Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science University, Amman, Jordan

    Maha Habash

  3. Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan

    Mutasem O. Taha

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  1. Sawsan Abuhamdah
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  2. Maha Habash
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  3. Mutasem O. Taha
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Correspondence to Mutasem O. Taha.

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Abuhamdah, S., Habash, M. & Taha, M.O. Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors. J Comput Aided Mol Des 27, 1075–1092 (2013). https://doi.org/10.1007/s10822-013-9699-6

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  • DOI: https://doi.org/10.1007/s10822-013-9699-6

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