The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies
Open accessAbstract
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 R 2 = 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Acetylcholine depletion in the central nervous system is involved in the pathophysiology of Alzheimer's disease.
“ACh depletion in the central nervous system has been involved in the pathophysiology noticed in AD [90]”
From Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review (2020) · cites this paper as [90]
Allicin is a membrane-permeable compound that can enter cells easily and interact with cellular thiols such as glutathione or cysteine residues in proteins as well as enzymes containing reactive cysteine, and this may be the potential interpretation of allicin's toxicity.
“Allicin is a membrane-permeable compound that can enter cells easily and interact with cellular thiols such as glutathione or cysteine residues in proteins [37,89,90] as well as enzymes containing reactive cysteine and this may be the potential interpretation of allicin’s toxicity [63].”
From Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review (2020) · cites this paper as [90]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196 · see citing works
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139 · see citing works
CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
Brooks, B., Bruccoleri, R., Olafson, B. D., States, D., Swaminathan, S., & Karplus, M. (1983) · Journal of Computational Chemistry · doi:10.1002/jcc.540040211 · Cited by 13,736 · see citing works
The price of innovation: new estimates of drug development costs
DiMasi, J. A., Hansen, R. W., & Grabowski, H. G. (2003) · Journal of Health Economics · doi:10.1016/s0167-6296(02)00126-1 · Cited by 4,265 · see citing works
Sussman, J. L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L., & Silman, I. (1991) · Science · doi:10.1126/science.1678899 · Cited by 2,711 · see citing works
Benchmarking sets for molecular docking.
Huang, N., Shoichet, B. K., & Irwin, J. J. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0608356 · Cited by 1,318 · see citing works
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Inestrosa, N. C., Alvarez, A. R., Pérez, C. A., Moreno, R. D., Vicente, M., Linker, C., Casanueva, O. I., Soto, C. A., & Garrido, J. (1996) · Neuron · doi:10.1016/s0896-6273(00)80108-7 · Cited by 1,107 · see citing works
Walters, W. P., Stahl, M. T., & Murcko, M. A. (1998) · Drug Discovery Today · doi:10.1016/s1359-6446(97)01163-x · Cited by 996 · see citing works
Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.
Harel, M., Schalk, I. J., Ehret‐Sabatier, L., Bouet, F., Goeldner, M. P., HIRTH, C. G., Axelsen, P. H., Silman, I., & Sussman, J. L. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.19.9031 · Cited by 902 · see citing works
Acetylcholinesterase: ‘classical’ and ‘non-classical’ functions and pharmacology
Silman, I., & Sussman, J. L. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2005.01.014 · Cited by 525 · see citing works
Marcu, M., Chadli, A., Bouhouche, I., Catelli, M., & Neckers, L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003701200 · Cited by 481 · see citing works
Selection criteria for drug‐like compounds
Muegge, I. (2003) · Medicinal Research Reviews · doi:10.1002/med.10041 · Cited by 418 · see citing works
A Structural Motif of Acetylcholinesterase That Promotes Amyloid β-Peptide Fibril Formation
Ferrari, G. V. D., Canales, M. A., Shin, I., Weiner, L. M., Silman, I., & Inestrosa, N. C. (2001) · Biochemistry · doi:10.1021/bi0101392 · Cited by 415 · see citing works
Harel, M., Quinn, D. M., Nair, H. K., Silman, I., & Sussman, J. L. (1996) · Journal of the American Chemical Society · doi:10.1021/ja952232h · Cited by 370 · see citing works
Pharmacophore Modeling and Three-dimensional Database Searching for Drug Design Using Catalyst
Kurogi, Y., & Güner, O. F. (2001) · Current Medicinal Chemistry · doi:10.2174/0929867013372481 · Cited by 357 · see citing works
Ordentlich, A., Barak, D., Kronman, C., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85305-x · Cited by 349 · see citing works
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents
Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T., & Clardy, J. (2000) · Structure · doi:10.1016/s0969-2126(00)00077-0 · Cited by 347 · see citing works
Structure of acetylcholinesterase complexed with (−)‐galanthamine at 2.3 Å resolution
Greenblatt, H. M., Kryger, G., Lewis, T., Silman, I., & Sussman, J. L. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01637-3 · Cited by 312 · see citing works
Kryger, G., Harel, M., Giles, K., et al. (2000) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444900010659 · Cited by 312 · see citing works
Ertl, P. (2002) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci0255782 · Cited by 294 · see citing works
Bolognesi, M. L., Cavalli, A., Valgimigli, L., Bartolini, M., Rosini, M., Andrisano, V., Recanatini, M., & Melchiorre, C. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm701225u · Cited by 262 · see citing works
Amyloid–cholinesterase interactions
Inestrosa, N. C., Dinamarca, M. C., & Alvarez, A. R. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2007.06238.x · Cited by 261 · see citing works
Rodrı́guez-Franco, M. I., Fernández‐Bachiller, M. I., Pérez, C., Hernández‐Ledesma, B., & Bartolomé, B. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050746d · Cited by 250 · see citing works
Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex
Rees, T. M. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00230-0 · Cited by 209 · see citing works
Camps, P., Formosa, X., Galdeano, C., Gómez, T., Muñoz-Torrero, D., Scarpellini, M., Viayna, E., Badía, A., Clos, M. V., Camins, A., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8001313 · Cited by 194 · see citing works
Barak, D., Kronman, C., Ordentlich, A., Ariel, N., Bromberg, A., Marcus, D., Lazar, A., Velan, B., & Avigdor Shafferman, C. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37371-4 · Cited by 193 · see citing works
Rizzo, S., Rivière, C., Piazzi, L., Bisi, A., Gobbi, S., Bartolini, M., Andrisano, V., Morroni, F., Tarozzi, A., Monti, J., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8002747 · Cited by 191 · see citing works
Rosini, M., Simoni, E., Bartolini, M., Cavalli, A., Ceccarini, L., Pascu, N., McClymont, D. W., Tarozzi, A., Bolognesi, M. L., Minarini, A., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800577j · Cited by 186 · see citing works
Camps, P., Formosa, X., Galdeano, C., Muñoz‐Torrero, D., Ramírez, L., Gómez, E., Isambert, N., Lavilla, R., Badı́a, A., Clos, M. V., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900859q · Cited by 174 · see citing works
Wei, D., Jiang, X., Zhou, L., Chen, J., Chen, Z., He, C., Yang, K., Liu, Y., Pei, J., & Lai, L. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8010096 · Cited by 141 · see citing works
Bolognesi, M. L., Banzi, R., Bartolini, M., Cavalli, A., Tarozzi, A., Andrisano, V., Minarini, A., Rosini, M., Tumiatti, V., Bergamini, C., et al. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm070559a · Cited by 134 · see citing works
Molecular Dynamics of Acetylcholinesterase
Shen, T., Tai, K., Henchman, R. H., & McCammon, J. A. (2002) · Accounts of Chemical Research · doi:10.1021/ar010025i · Cited by 129 · see citing works
Three-dimensional structure of a complex of E2020 with acetylcholinesterase from Torpedo californica
Kryger, G., Silman, I., & Sussman, J. L. (1998) · Journal of Physiology-Paris · doi:10.1016/s0928-4257(98)80008-9 · Cited by 104 · see citing works
Clement, O. O., Freeman, C. M., Hartmann, R. W., Handratta, V. D., Vasaitis, T. S., Brodie, A. M. H., & Njar, V. C. O. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm020576u · Cited by 83 · see citing works
Piazzi, L., Cavalli, A., Belluti, F., Bisi, A., Gobbi, S., Rizzo, S., Bartolini, M., Andrisano, V., Recanatini, M., & Rampa, A. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm070100g · Cited by 82 · see citing works
Piazzi, L., Belluti, F., Bisi, A., Gobbi, S., Rizzo, S., Bartolini, M., Andrisano, V., Recanatini, M., & Rampa, A. (2006) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2006.09.026 · Cited by 67 · see citing works
A Modular Treatment of Molecular Traffic Through the Active Site of Cholinesterase
Botti, S. A., Felder, C. E., Lifson, S., Sussman, J. L., & Silman, I. (1999) · Biophysical Journal · doi:10.1016/s0006-3495(99)77080-3 · Cited by 60 · see citing works
Rees, T. M., Berson, A., Sklan, E. H., Younkin, L. H., Younkin, S. G., Brimijoin, S., & Soreq, H. (2005) · Current Alzheimer Research · doi:10.2174/1567205054367847 · Cited by 60 · see citing works
Campiani, G., Fattorusso, C., Butini, S., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm049510k · Cited by 59 · see citing works
Tumiatti, V., Milelli, A., Minarini, A., Rosini, M., Bolognesi, M. L., Micco, M., Andrisano, V., Bartolini, M., Mancini, F., Recanatini, M., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8009684 · Cited by 58 · see citing works
Butini, S., Campiani, G., Borriello, M., Gemma, S., Panico, A., Persico, M., Catalanotti, B., Ros, S., Brindisi, M., Agnusdei, M., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701253t · Cited by 58 · see citing works
Xu, Y., Colletier, J., Jiang, H., et al. (2008) · Protein Science · doi:10.1110/ps.083453808 · Cited by 51 · see citing works
Silman, I., Harel, M., Axelsen, P. H., et al. (1994) · Biochemical Society Transactions · doi:10.1042/bst0220745 · Cited by 48 · see citing works
Pathways of ligand clearance in acetylcholinesterase by multiple copy sampling
Belle, D. V., Maria, L. D., Iurcu‐Mustata, G., & Wodak, S. J. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.3698 · Cited by 32 · see citing works
Lakshmi, P. J., Suneel Kumar, B. V. S., Nayana, R. S., et al. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.06.069 · Cited by 30 · see citing works
Muñoz, J. A., Lopez, J., Orozco, M., et al. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043383386 · Cited by 30 · see citing works
Villoutreix, B. O., Dahlb�ck, B., Borgel, D., Gandrille, S., & Muller, Y. A. (2001) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(20010501)43:2 · Cited by 26 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Poptodorov K Luu T Hoffmann RD Langer T, Hoffmann RD In Methods and principles in Medicinal Chemistry, Pharmacophores and Pharmacophores Searches 2006 2 Germany: Wiley-VCH:Weinheim 17 47
Cited by
Sorted by citations
Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review
El-Saber Batiha, G., Magdy Beshbishy, A., G. Wasef, L., Elewa, Y. H. A., A. Al-Sagan, A., Abd El-Hack, M. E., Taha, A. E., M. Abd-Elhakim, Y., & Prasad Devkota, H. (2020) · Nutrients · doi:10.3390/nu12030872 · Cited by 931 · see citing works
Alarcón, J., Cespedes, C. L., Muñoz, E., Balbontin, C., Valdes, F., Gutierrez, M., Astudillo, L., & Seigler, D. S. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b04168 · Cited by 33 · see citing works
Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo
Stern, N., Gacs, A., Tátrai, E., Flachner, B., Hajdú, I., Dobi, K., Bágyi, I., Dormán, G., Lőrincz, Z., Cseh, S., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113098 · Cited by 35 · see citing works
- Authors
- Lu, S.-H., Wu, J. W., Liu, H.-L., Zhao, J.-H., Liu, K.-T., Chuang, C.-K., Lin, H.-Y., Tsai, W.-B., & Ho, Y.
- Affiliations
- National Taipei University of Technology (TW)
- Institute of Nuclear Energy Research (TW)
- Fu Jen Catholic University (TW)
- National Taiwan University (TW)
- Taipei Medical University (TW)
- Corresponding author
- Liu, Hsuan-Liang
- Venue
- Journal of Biomedical Science
- Published
- 2011-01-21
- Volume
- 18
- Issue
- 1
- Pages
- 8-8
- ISSN
- 1021-7770 (ISSN-L)
- 1423-0127
- PMC
- PMC3036604
- OpenAlex
- W2126661983
- Cited by
- 204
- References
- 48
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 27 · 2021: 15 · 2020: 8 · 2019: 13 · 2018: 19 · 2017: 16 · 2016: 14 · 2015: 11 · 2014: 7 · 2013: 10 · 2012: 6
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Journal of Biomedical Science (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Taipei Medical University Repository (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Science Council
- Taipei Medical University
- Institute of Nuclear Energy Research
- National Taipei University of Technology
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- acetylcholinesterase inhibitors, Alzheimer's disease, pharmacophore modeling, virtual screening, molecular docking, NCI database, amyloid-beta toxicity, cholinergic system, drug discovery
- MeSH terms
- Acetylcholinesterase, Alzheimer Disease, Cholinesterase Inhibitors, Humans, Models, Biological, Models, Molecular, Neurons, Databases, Factual, Amyloid beta-Protein Precursor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review