Login Register Cart 0
Generic placeholder image

Central Nervous System Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In silico Study of Acetylcholinesterase and Beta-secretase Inhibitors: Potential Multitarget Anti-Alzheimer’s Agents

Author(s): Daniel Castro da Costa, Hueldem Ronam Cristo Teixeira, Raí Campos Silva, Isaque Antonio Galindo Francischini, Carlos Henrique Tomich de Paula da Silva and Lorane Izabel da Silva Hage-Melim*

Volume 22, Issue 2, 2022

Published on: 17 June, 2022

Page: [139 - 150] Pages: 12

DOI: 10.2174/1871524922666220517110606

Price: $65

Abstract

Background: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters.

Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs.

Methods: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed.

Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets.

Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.

Keywords: Alzheimer's disease, anticholinesterases, β-secretase, molecular modeling, molecular docking, multitarget drugs.

« Previous Next »
Graphical Abstract

[1]
Afshari, A.R.; Sadeghnia, H.R.; Mollazadeh, H. A Review on Potential Mechanisms of Terminalia chebula in Alzheimer’s Disease. Adv. Pharmacol. Sci., 2016, 2016, 8964849.
[http://dx.doi.org/10.1155/2016/8964849] [PMID: 26941792]
[2]
Guimarães, L.; Lazzaratti, C. Doença de alzheimer e diabetes mellitus tipo 2: Relações metabólicas e neurodegenerativas, R. Perspect. Ci. e Saúde, 2017, 2(1), 113-123.
[3]
Mendiola-Precoma, J.; Berumen, L.C.; Padilla, K.; Garcia-alcocer, G. therapies for prevention and treatment of alzheimer’s disease. BioMed Res. Int., 2016, 2016, 2589276.
[http://dx.doi.org/10.1155/2016/2589276] [PMID: 27547756]
[4]
Lima, D.A. Tratamento Farmacológico da Doença de Alzheimer; Revista do Hospital Universitário Pedro Ernest, 2008, pp. 78-87.
[5]
Tewari, D.; Stankiewicz, A.M.; Mocan, A.; Sah, A.N.; Tzvetkov, N.T.; Huminiecki, L.; Horbańczuk, J.O.; Atanasov, A.G. Ethnopharmacological approaches for dementia therapy and significance of natural products and herbal drugs. Front. Aging Neurosci., 2018, 10, 3.
[http://dx.doi.org/10.3389/fnagi.2018.00003] [PMID: 29483867]
[6]
Baskaran, X.R.; Geo Vigila, A.V.; Zhang, S.Z.; Feng, S.X.; Liao, W.B. A review of the use of pteridophytes for treating human ailments. Biomed. Biotechnol., 2018, 19(2), 85-119.
[http://dx.doi.org/10.1631/jzus.B1600344] [PMID: 29405039]
[7]
Picanço, L.C.S. Planejamento de candidatos a fármacos multialvo inibidores de acetilcolinesterase (AChE) e glicogênio sintase quinase-3β (GESK-3β) para tratamento da doença de Alzheimer, Dissertação (Ciências Farnacêuticas) - Farmácia, Universidade Federal do Amapá, Macapá, 2018.
[8]
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14(17), 1829-1852.
[http://dx.doi.org/10.2174/092986707781058805] [PMID: 17627520]
[9]
Batista, G. da C.; Lima, R.A.; Crisóstomo, S.L.C.; Marinho, M.M.; Marinho, E.S. Softwares Para O Ensino De Química. Chemsketch Um Poderoso Recurso Didático, 2016, 5, 1.
[10]
Frisch, M.J.G.; Trucks, W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Montgomery, J.A.; Vreven, T., Jr; Kudin, K.N.; Burant, J.C.; Millam, J.M.; Iyengar, S.S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J.E.; Hratchian, H.P.; Cross, J.B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Ayala, P.Y.; Morokuma, K.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Zakrzewski, V.G.; Dapprich, S.; Daniels, A.D.; Strain, M.C.; Farkas, O.; Malick, D.K.; Rabuck, A.D.; Raghavachari, K.; Foresman, J.B.; Ortiz, J.V.; Cui, Q.; Baboul, A.G.; Clifford, S.; Cioslowski, J.; Stefanov, B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R.L.; Fox, D.J.; Keith, T.; Al-Laham, M.A.; Peng, C.Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.M.W.; Johnson, B.; Chen, W.; Wong, M. Gaussian 03, Revision A.1; Gaussian, Inc.: Pittsburgh PA, 2003.
[11]
Ozela, P.F.; Picanço, L.C.S.; Souza, L.R.; Barbosa, R.C.; Ferreira, J.V.; Silva, C.H.T.P.; Rodrigues dos Santos, C.B.; Hage-Melim, L.I.S. Evaluation of Computational Method from Crystallofraphic Structure of Galantamine for Molecular Modeling of Drug Candidates Anti-Alzheimer’s Disease. J. Comput. Theor. Nanosci., 2019, 16(7), 2673-2686.
[http://dx.doi.org/10.1166/jctn.2019.8221]
[12]
Kennedy, M.E.; Stamford, A.W.; Chen, X.; Cox, K.; Cumming, J.N.; Dockendorf, M.F.; Egan, M.; Ereshefsky, L.; Hodgson, R.A.; Lynn, A.H.; Stanford, J.; Kleijn, H.J.; Kuvelkar, R.; Li, W.; Mattson, B.A.; Mei, H.; Palcza, J.; Scott, J.D.; Tanen, M.; Troyer, M.D.; Tseng, J.L.; Stone, J.A.; Parker, E.M.; Forman, M.S. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS b-Amyloid in animal models and in Alzheimer’s disease patients. Sci. Transl. Med., 2016, 8(363), 1-14.
[http://dx.doi.org/10.1126/scitranslmed.aad9704] [PMID: 27807285]
[13]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[14]
Schneidman-Duhovny, D.; Dror, O.; Inbar, Y.; Nussinov, R.; Wolfson, H.J. PharmaGist: A webserver for ligand-based pharmacophore detection. Nucleic Acids Res, 2008, 36(Web Server issue), W223-8.
[http://dx.doi.org/10.1093/nar/gkn187] [PMID: 18424800]
[15]
Quintanova, R.I.C. Novos compostos híbridos com potencial ação neuroprotetora, Dissertação - Departamento de Química e Bioquímica - Faculdade de Ciências - Universidade de Lisboa, Lisboa, 2013.
[16]
Sanderson, D.M.; Earnshaw, C.G. Computer prediction of possible toxic action from chemical structure; the DEREK system. Hum. Exp. Toxicol., 1991, 10(4), 261-273.
[http://dx.doi.org/10.1177/096032719101000405] [PMID: 1679649]
[17]
Gupta, S.; Mohan, C.G. Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore models and sequential virtual screening. BioMed Res. Int., 2014, 2014, 291214.
[http://dx.doi.org/10.1155/2014/291214] [PMID: 25050335]
[18]
Cole, J.C.; Murray, C.W.; Nissink, J.W.M.; Taylor, R.D.; Taylor, R. Comparing protein-ligand docking programs is difficult. Proteins, 2005, 60(3), 325-332.
[http://dx.doi.org/10.1002/prot.20497] [PMID: 15937897]
[19]
Verhoeckx, K.; Cotter, P.; López-Expósito, I.; Kleiveland, C.; Lea, T.; Mackie, A.; Requena, T.; Swiatecka, D.; Wichers, H. The impact of food bioactives on health: In vitro and ex vivo models; Springer, 2015.
[http://dx.doi.org/10.1007/978-3-319-16104-4]
[20]
Garg, P.; Verma, J. In silico prediction of blood brain barrier permeability: An artificial neural network model. J. Chem. Inf. Model., 2006, 46(1), 289-297.
[http://dx.doi.org/10.1021/ci050303i] [PMID: 16426064]
[21]
Hitchcock, S.A.; Pennington, L.D. Structure-brain exposure relationships. J. Med. Chem., 2006, 49(26), 7559-7583.
[http://dx.doi.org/10.1021/jm060642i] [PMID: 17181137]
[22]
Pajouhesh, H.; Lenz, G.R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005, 2(4), 541-553.
[http://dx.doi.org/10.1602/neurorx.2.4.541] [PMID: 16489364]
[23]
Chaudhary, K.K.; Mishra, N. Review on molecular docking: Novel tool for drug discovery. JSM Chem., 2016, 1029.
[24]
Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery, Curr. Comput. Curr. Computeraided Drug Des., 2012, 7(2), 146-157.
[http://dx.doi.org/10.2174/157340911795677602]
[25]
Fraga, C.A.M. Drug hybridization strategies: Before or after lead identification? Expert Opin. Drug Discov., 2009, 4(6), 605-609.
[http://dx.doi.org/10.1517/17460440902956636] [PMID: 23489153]
[26]
Simoes, M.R.; Viegas, F.D.P.; Moreira, M.S.; Silva, M.F.; Riquiel, M.M.; Rosa, P.M.; Castelli, M.R.; Santos, M.H.; Soares, M.G.; Viegas, C. Jr Donepezil: An important prototype to the design of new drug candidates for alzheimer’s disease, mini-reviews. Med. Chem. 2014. 14, 1-, 2-19
[27]
Han, J.; Ji, Y.; Youn, K.; Lim, G.; Lee, J.; Kim, D.H.; Jun, M. Baicalein as a potential inhibitor against bace1 and ache: Mechanistic comprehension through in vitro and computational approaches. Nutrients, 2019, 11(11), 1-11.
[http://dx.doi.org/10.3390/nu11112694] [PMID: 31703329]
[28]
Hassan, M.; Shahzadi, S.; Seo, S.Y.; Alashwal, H.; Zaki, N.; Moustafa, A.A. Molecular docking and dynamic simulation of AZD3293 and Solanezumab Effects against BACE1 to treat alzheimer’s disease. Front. Comput. Neurosci., 2018, 12, 34.
[http://dx.doi.org/10.3389/fncom.2018.00034] [PMID: 29910719]
[29]
Gupta, S.; Fallarero, A.; Järvinen, P.; Karlsson, D.; Johnson, M.S.; Vuorela, P.M.; Mohan, C.G. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques. Bioorg. Med. Chem. Lett., 2011, 21(4), 1105-1112.
[http://dx.doi.org/10.1016/j.bmcl.2010.12.131] [PMID: 21273074]
[30]
Xie, Q.; Zheng, Z.; Shao, B.; Fu, W.; Xia, Z.; Li, W.; Sun, J.; Zheng, W.; Zhang, W.; Sheng, W.; Zhang, Q.; Chen, H.; Wang, H.; Qiu, Z. Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 659-671.
[http://dx.doi.org/10.1080/14756366.2016.1265521] [PMID: 28274151]
[31]
Kumar, S.; Chowdhury, S.; Kumar, S. In silico repurposing of antipsychoticdrugs for Alzheimer’s disease; BMC Neurosc, 2017.
[32]
Huang, H.; Chen, H.; Lee, C.; Chen, C.Y. Computational design of apolipoprotein e4 inhibitors for alzheimer’s disease therapy from traditional. Chinese Medicine, 2014.
[33]
Azam, F.; Amer, A.M.; Abulifa, A.R.; Elzwawi, M.M. Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: A computational investigation. Drug Des. Devel. Ther., 2014, 8, 2045-2059.
[http://dx.doi.org/10.2147/DDDT.S67778] [PMID: 25364231]
[34]
Jackisch, R.; Förster, S.; Kammerer, M.; Rothmaier, A.K.; Ehret, A.; Zentner, J.; Feuerstein, T.J. Inhibitory potency of choline esterase inhibitors on acetylcholine release and choline esterase activity in fresh specimens of human and rat neocortex. J. Alzheimers Dis., 2009, 16(3), 635-647.
[http://dx.doi.org/10.3233/JAD-2009-1008] [PMID: 19276558]
[35]
Jung, M.; Park, M. Acetylcholinesterase inhibition by flavonoids from Agrimonia pilosa. Molecules, 2007, 12(9), 2130-2139.
[http://dx.doi.org/10.3390/12092130] [PMID: 17962731]
[36]
Lim, D.K.; Lee, Y.B.; Kim, H.S. Effects of dehydroevodiamine exposure on glutamate release and uptake in the cultured cerebellar cells. Neurochem. Res., 2004, 29(2), 407-411.
[http://dx.doi.org/10.1023/B:NERE.0000013745.17014.a3] [PMID: 15002738]

Rights & Permissions Print Cite
Article Metrics
12
1
© 2024 Bentham Science Publishers | Privacy Policy