Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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

Identification of Butyrylcholinesterase and Monoamine Oxidase B Targeted Ligands and their Putative Application in Alzheimer’s Treatment: A Computational Strategy

Author(s): Nasimudeen R. Jabir, Md. Tabish Rehman, Shams Tabrez*, Raed F. Alserihi, Mohamed F. AlAjmi, Mohd Shahnawaz Khan, Fohad Mabood Husain and Bakrudeen Ali Ahmed*

Volume 27, Issue 20, 2021

Published on: 26 February, 2021

Page: [2425 - 2434] Pages: 10

DOI: 10.2174/1381612827666210226123240

Price: $65

Abstract

Background: With the burgeoning worldwide aging population, the incidence of Alzheimer’s disease (AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase) and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes, namely butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly meet the unmet medical need of better AD treatment.

Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAOB using PyRx-Python prescription 0.8. The visualization of the active interaction of studied compounds with targeted proteins was performed by Discovery Studio 2020 (BIOVIA).

Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to -11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand 6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and -10.4 kcal mol, respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed the formation of a stable complex.

Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD drugs generated on this chemical scaffold.

Keywords: Alzheimer's disease, butylrylcholinesterase, drug development, molecular docking and simulation, monoamine oxidase A, monoamine oxidase B, multi-targeted ligands.

« Previous
[1]
Islam BU, Jabir NR, Tabrez S. The role of mitochondrial defects and oxidative stress in Alzheimer’s disease. J Drug Target 2019; 27(9): 932-42.
[http://dx.doi.org/10.1080/1061186X.2019.1584808] [PMID: 30775938]
[2]
Obrenovich M, Tabrez S, Siddiqui B, McCloskey B, Perry G. The microbiota-gut-brain axis-heart shunt part II: prosaic foods and the brain-heart connection in alzheimer disease. Microorganisms 2020; 8(4): e493.
[http://dx.doi.org/10.3390/microorganisms8040493] [PMID: 32244373]
[3]
Haque RU, Levey AI. Alzheimer’s disease: A clinical perspective and future nonhuman primate research opportunities. Proc Natl Acad Sci USA 2019; 116: 26224-9.
[http://dx.doi.org/10.1073/pnas.1912954116] [PMID: 31871211]
[4]
Cummings J, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 76.
[http://dx.doi.org/10.1186/s13195-019-0529-5] [PMID: 31470905]
[5]
Loera-Valencia R, Cedazo-Minguez A, Kenigsberg PA, et al. Current and emerging avenues for Alzheimer’s disease drug targets. J Intern Med 2019; 286(4): 398-437.
[http://dx.doi.org/10.1111/joim.12959] [PMID: 31286586]
[6]
Liu P-P, Xie Y, Meng X-Y, Kang J-S. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther 2019; 4: 1-22.
[http://dx.doi.org/10.1038/s41392-019-0063-8]
[7]
Grieg NH, Kamal MA, Jabir NR, et al. Chapter 6 - specific cholinesterase inhibitors: a potential tool to assist in management of alzheimer disease.Drug Design and Discovery in Alzheimer's Disease. Elsevier 2014; pp. 366-86.
[8]
Ul Islam B, Khan MS, Jabir NR, Kamal MA, Tabrez S. Elucidating treatment of alzheimer’s disease via different receptors. Curr Top Med Chem 2017; 17(12): 1400-7.
[http://dx.doi.org/10.2174/1568026617666170103163715] [PMID: 28049400]
[9]
Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem 2014; 21(19): 2208-17.
[http://dx.doi.org/10.2174/0929867321666131227161303] [PMID: 24372221]
[10]
Ashraf GM, Greig NH, Khan TA, et al. Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 2014; 13(7): 1280-93.
[http://dx.doi.org/10.2174/1871527313666140917095514] [PMID: 25230234]
[11]
Jabir NR, Khan FR, Tabrez S. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease. CNS Neurosci Ther 2018; 24(9): 753-62.
[http://dx.doi.org/10.1111/cns.12971] [PMID: 29770579]
[12]
Chen X-Q, Mobley WC. Exploring the pathogenesis of alzheimer disease in basal forebrain cholinergic neurons: converging insights from alternative hypotheses. Front Neurosci 2019; 13: 446.
[http://dx.doi.org/10.3389/fnins.2019.00446] [PMID: 31133787]
[13]
Jabir NR, Kamal MA, Abuzenadah AM, et al. Alzheimer’s and type 2 diabetes treatment via common enzyme targeting. CNS Neurol Disord Drug Targets 2014; 13(2): 299-304.
[http://dx.doi.org/10.2174/18715273113126660145] [PMID: 24059315]
[14]
Yiannopoulou KG, Papageorgiou SG. Current and future treatments in alzheimer disease: an update. J Cent Nerv Syst Dis 2020; 12: 1179573520907397.
[http://dx.doi.org/10.1177/1179573520907397] [PMID: 32165850]
[15]
Ashraf GM, Tabrez S, Jabir NR, et al. An overview on global trends in nanotechnological approaches for alzheimer therapy. Curr Drug Metab 2015; 16(8): 719-27.
[http://dx.doi.org/10.2174/138920021608151107125757] [PMID: 26560324]
[16]
Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 2020; 27(1): 18.
[http://dx.doi.org/10.1186/s12929-019-0609-7] [PMID: 31906949]
[17]
Hughes RE, Nikolic K, Ramsay RR. One for all? hitting multiple alzheimer’s disease targets with one drug. Front Neurosci 2016; 10: 177.
[http://dx.doi.org/10.3389/fnins.2016.00177] [PMID: 27199640]
[18]
Kenakin TP. Chapter 6 - enzymes as drug targets.Pharmacology in Drug Discovery. Academic Press: Boston 2012; pp. 105-24.
[19]
Deng Y-H, Wang N-N, Zou Z-X, et al. Multi-target screening and experimental validation of natural products from selaginella plants against alzheimer’s disease. Front Pharmacol 2017; 8: 539.
[http://dx.doi.org/10.3389/fphar.2017.00539] [PMID: 28890698]
[20]
Nordberg A, Ballard C, Bullock R, Darreh-Shori T, Somogyi M. A review of butyrylcholinesterase as a therapeutic target in the treatment of alzheimer’s disease. The Primary Care Companion for CNS Disorders 2013; 15.
[http://dx.doi.org/10.4088/PCC.12r01412]
[21]
Riederer P, Danielczyk W, Grünblatt E. Monoamine oxidase-B inhibition in Alzheimer’s disease. Neurotoxicology 2004; 25(1-2): 271-7.
[http://dx.doi.org/10.1016/S0161-813X(03)00106-2] [PMID: 14697902]
[22]
Lin X, Li X, Lin X. A review on applications of computational methods in drug screening and design. Molecules 2020; 25(6): 1375.
[http://dx.doi.org/10.3390/molecules25061375] [PMID: 32197324]
[23]
Ramsay RR, Popovic-Nikolic MR, Nikolic K, Uliassi E, Bolognesi ML. A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med 2018; 7(1): 3.
[http://dx.doi.org/10.1186/s40169-017-0181-2] [PMID: 29340951]
[24]
Jabir NR, Shakil S, Tabrez S, Khan MS, Rehman MT, Ahmed BA. In silico screening of glycogen synthase kinase-3β targeted ligands against acetylcholinesterase and its probable relevance to Alzheimer’s disease. J Biomol Struct Dyn 2020; 1-10.
[http://dx.doi.org/10.1080/07391102.2020.1784796] [PMID: 32588759]
[25]
Nastasă C, Tamaian R, Oniga O, Tiperciuc B. 5-Arylidene(chromenyl-methylene)-thiazolidinediones: Potential New Agents against Mutant Oncoproteins K-Ras, N-Ras and B-Raf in Colorectal Cancer and Melanoma. Medicina (Kaunas) 2019; 55(4): 85.
[http://dx.doi.org/10.3390/medicina55040085] [PMID: 30935124]
[26]
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[27]
Shafiu S, Edache EI, Sani U, Abatyough M. Docking and virtual screening studies of tetraketone derivatives as tyrosine kinase (EGFR) Inhibitors: a rational approach to anti-fungi drug design. Journal of Pharmaceutical and Medicinal Research 2017; 3: 78-80.
[28]
Rizvi SMD, Shaikh S, Naaz D, et al. Kinetics and molecular docking study of an anti-diabetic drug glimepiride as acetylcholinesterase inhibitor: implication for alzheimer’s disease-diabetes dual therapy. Neurochem Res 2016; 41(6): 1475-82.
[http://dx.doi.org/10.1007/s11064-016-1859-3] [PMID: 26886763]
[29]
Shaker B, Yu M-S, Lee J, Lee Y, Jung C, Na D. User guide for the discovery of potential drugs via protein structure prediction and ligand docking simulation. J Microbiol 2020; 58(3): 235-44.
[http://dx.doi.org/10.1007/s12275-020-9563-z] [PMID: 32108318]
[30]
AlAjmi MF, Rehman MT, Hussain A, Rather GM. Pharmacoinformatics approach for the identification of Polo-like kinase-1 inhibitors from natural sources as anti-cancer agents. Int J Biol Macromol 2018; 116: 173-81.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.05.023] [PMID: 29738867]
[31]
Rehman MT, AlAjmi MF, Hussain A, Rather GM, Khan MA. High-throughput virtual screening, molecular dynamics simulation, and enzyme kinetics identified ZINC84525623 as a potential inhibitor of NDM-1. Int J Mol Sci 2019; 20(4): 819.
[http://dx.doi.org/10.3390/ijms20040819] [PMID: 30769822]
[32]
Brańka AC. Nose-Hoover chain method for nonequilibrium molecular dynamics simulation. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 2000; 61(5A): 4769-73.
[http://dx.doi.org/10.1103/PhysRevE.61.4769] [PMID: 11031517]
[33]
Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys 1994; 101: 4177-89.
[http://dx.doi.org/10.1063/1.467468]
[34]
Rabbani N, Tabrez S, Islam BU, et al. Characterization of colchicine binding with normal and glycated albumin: In vitro and molecular docking analysis. J Biomol Struct Dyn 2018; 36(13): 3453-62.
[http://dx.doi.org/10.1080/07391102.2017.1389661] [PMID: 28990867]
[35]
Rehman MT, Shamsi H, Khan AU. Insight into the binding mechanism of imipenem to human serum albumin by spectroscopic and computational approaches. Mol Pharm 2014; 11(6): 1785-97.
[http://dx.doi.org/10.1021/mp500116c] [PMID: 24745377]
[36]
Wolfe MS. γ-Secretase inhibitors and modulators for Alzheimer’s disease. J Neurochem 2012; 120(Suppl. 1): 89-98.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07501.x] [PMID: 22122056]
[37]
Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997; 336(17): 1216-22.
[http://dx.doi.org/10.1056/NEJM199704243361704] [PMID: 9110909]
[38]
Dong H, Yuede CM, Coughlan CA, Murphy KM, Csernansky JG. Effects of donepezil on amyloid-beta and synapse density in the Tg2576 mouse model of Alzheimer’s disease. Brain Res 2009; 1303: 169-78.
[http://dx.doi.org/10.1016/j.brainres.2009.09.097] [PMID: 19799879]
[39]
Kumar A, Pintus F, Di Petrillo A, et al. Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer’s disease. Sci Rep 2018; 8(1): 4424.
[http://dx.doi.org/10.1038/s41598-018-22747-2] [PMID: 29535344]
[40]
Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol Med Rep 2019; 20(2): 1479-87.
[PMID: 31257471]
[41]
Park J-H, Ju YH, Choi JW, et al. Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. Sci Adv 2019; 5(3): eaav0316.
[http://dx.doi.org/10.1126/sciadv.aav0316] [PMID: 30906861]
[42]
Maia MA, Sousa E. BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease. Pharmaceuticals (Basel) 2019; 12(1): 41.
[http://dx.doi.org/10.3390/ph12010041] [PMID: 30893882]
[43]
Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH. BACE1 inhibitors: Current status and future directions in treating Alzheimer’s disease. Med Res Rev 2020; 40(1): 339-84.
[http://dx.doi.org/10.1002/med.21622] [PMID: 31347728]
[44]
Bartolini M, Bertucci C, Cavrini V, Andrisano V. beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 2003; 65(3): 407-16.
[http://dx.doi.org/10.1016/S0006-2952(02)01514-9] [PMID: 12527333]
[45]
Aamir M, Singh VK, Dubey MK, et al. In silico Prediction, characterization, molecular docking, and dynamic studies on fungal SDRs as novel targets for searching potential fungicides against fusarium wilt in tomato. Front Pharmacol 2018; 9: 1038.
[http://dx.doi.org/10.3389/fphar.2018.01038] [PMID: 30405403]
[46]
Shen M, Zhou S, Li Y, Pan P, Zhang L, Hou T. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. Mol Biosyst 2013; 9(3): 361-74.
[http://dx.doi.org/10.1039/c2mb25408e] [PMID: 23340525]
[47]
Du X, Li Y, Xia Y-L, et al. Insights into protein-ligand interactions: mechanisms, models, and methods. Int J Mol Sci 2016; 17(2): 144.
[http://dx.doi.org/10.3390/ijms17020144] [PMID: 26821017]
[48]
Francoeur PG, Masuda T, Sunseri J, et al. Three-dimensional convolutional neural networks and a cross-docked data set for structure-based drug design. J Chem Inf Model 2020; 60(9): 4200-15.
[http://dx.doi.org/10.1021/acs.jcim.0c00411] [PMID: 32865404]
[49]
Nicolet Y, Lockridge O, Masson P, Fontecilla-Camps JC, Nachon F. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J Biol Chem 2003; 278(42): 41141-7.
[http://dx.doi.org/10.1074/jbc.M210241200] [PMID: 12869558]
[50]
Krátký M, Štěpánková Š, Vorčáková K, Švarcová M, Vinšová J. Novel cholinesterase inhibitors based on O-Aromatic N,N-Disubstituted carbamates and thiocarbamates. Molecules 2016; 21(2): 191.
[http://dx.doi.org/10.3390/molecules21020191] [PMID: 26875979]
[51]
Shalaby R, Petzer JP, Petzer A, et al. SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs. J Enzyme Inhib Med Chem 2019; 34(1): 863-76.
[http://dx.doi.org/10.1080/14756366.2019.1593158] [PMID: 30915862]
[52]
Rahman S, Rehman MT, Rabbani G, et al. Insight of the interaction between 2,4-thiazolidinedione and human serum albumin: a spectroscopic, thermodynamic and molecular docking study. Int J Mol Sci 2019; 20(11): 2727.
[http://dx.doi.org/10.3390/ijms20112727] [PMID: 31163649]
[53]
Shamsi A, Mohammad T, Khan MS, et al. Unraveling binding mechanism of alzheimer’s drug rivastigmine tartrate with human transferrin: molecular docking and multi-spectroscopic approach towards neurodegenerative diseases. Biomolecules 2019; 9(9): 495.
[http://dx.doi.org/10.3390/biom9090495] [PMID: 31533274]
[54]
Shamsi A, Mohammad T, Anwar S, et al. Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy. Biosci Rep 2020; 40(6): BSR20201256.
[http://dx.doi.org/10.1042/BSR20201256] [PMID: 32441299]
[55]
Mohammad T, Shamsi A, Anwar S, et al. Identification of high-affinity inhibitors of SARS-CoV-2 main protease: Towards the development of effective COVID-19 therapy. Virus Res 2020; 288: 198102.
[http://dx.doi.org/10.1016/j.virusres.2020.198102] [PMID: 32717346]

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