The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies.
BACKGROUND
Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD.


METHODS
In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors.


RESULTS
The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R² = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site.


CONCLUSIONS
The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.
Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E, Rd., Taipei, 10608, Taiwan.
Shin-Hua
SH
Lu
Josephine W
JW
Wu
Hsuan-Liang
HL
Liu
Jian-Hua
JH
Zhao
Kung-Tien
KT
Liu
Chih-Kuang
CK
Chuang
Hsin-Yi
HY
Lin
Wei-Bor
WB
Tsai
Yih
Y
Ho
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D016208:Databases, Factual; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009474:Neurons / Q000201:enzymology
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
Biochem Soc Trans. 1994 Aug;22(3):745-9
7821677
J Med Chem. 2007 Oct 4;50(20):4882-97
17850125
J Med Chem. 2008 Jun 12;51(11):3154-70
18479118
Structure. 2000 Jan 15;8(1):25-33
10673429
J Med Chem. 2007 Dec 27;50(26):6446-9
18047264
FEBS Lett. 1999 Dec 17;463(3):321-6
10606746
Acta Crystallogr D Biol Crystallogr. 2000 Nov;56(Pt 11):1385-94
11053835
J Chem Inf Comput Sci. 2003 Mar-Apr;43(2):374-80
12653499
Biophys J. 1999 Nov;77(5):2430-50
10545346
J Health Econ. 2003 Mar;22(2):151-85
12606142
J Med Chem. 2008 May 22;51(10):2883-6
18419109
J Med Chem. 2006 Nov 16;49(23):6789-801
17154509
Neurobiol Aging. 2003 Oct;24(6):777-87
12927760
J Biol Chem. 2000 Nov 24;275(47):37181-6
10945979
Bioorg Med Chem. 2009 Aug 15;17(16):6040-7
19631549
J Biol Chem. 1993 Aug 15;268(23):17083-95
8349597
J Mol Biol. 2000 May 12;298(4):705-26
10788331
J Med Chem. 2003 Jun 5;46(12):2345-51
12773039
Bioorg Med Chem. 2007 Jan 1;15(1):575-85
17008100
Curr Med Chem. 2001 Jul;8(9):1035-55
11472240
J Biol Chem. 1994 Mar 4;269(9):6296-305
8119978
J Med Chem. 2006 Jan 26;49(2):459-62
16420031
J Med Chem. 2008 Dec 25;51(24):7882-8
19090779
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
J Med Chem. 2008 Jun 26;51(12):3588-98
18517184
Curr Alzheimer Res. 2005 Jul;2(3):291-300
15974894
Curr Pharm Des. 2004;10(25):3131-40
15544503
Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5
8415649
J Med Chem. 2009 Sep 10;52(17):5365-79
19663388
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
11259830
J Med Chem. 2008 Aug 14;51(15):4381-4
18605718
Med Res Rev. 2003 May;23(3):302-21
12647312
J Med Chem. 2005 Mar 24;48(6):1919-29
15771436
FEBS J. 2008 Feb;275(4):625-32
18205831
J Med Chem. 2008 Nov 27;51(22):7308-12
18954037
J Med Chem. 2007 Aug 23;50(17):4250-4
17655212
Science. 1991 Aug 23;253(5022):872-9
1678899
Protein Sci. 2008 Apr;17(4):601-5
18359854
Proteins. 2001 May 1;43(2):113-24
11276081
Neuron. 1996 Apr;16(4):881-91
8608006
Biochemistry. 2001 Sep 4;40(35):10447-57
11523986
J Med Chem. 2008 Feb 14;51(3):347-72
18181565
Acc Chem Res. 2002 Jun;35(6):332-40
12069617
Curr Opin Pharmacol. 2005 Jun;5(3):293-302
15907917
J Physiol Paris. 1998 Jun-Aug;92(3-4):191-4
9789806