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Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Computer-Aided Identification of Cholinergic and Monoaminergic Inhibitory Flavonoids from Hibiscus sabdariffa L.

Author(s): Kayode Ezekiel Adewole, Gideon Ampoma Gyebi, Ahmed Adebayo Ishola and Ayodeji Osmund Falade*

Volume 19, Issue 5, 2022

Published on: 07 July, 2022

Article ID: e250522205232 Pages: 16

DOI: 10.2174/1570163819666220525101039

Price: $65

Abstract

Background: The reduced levels of acetylcholine and dopamine lead to Alzheimer’s disease (AD) and Parkinson’s disease PD, respectively, due to the action of cholinesterase and monoamine oxidase B.

Methods: Therapeutic options for AD and PD involve respective cholinergic and monoaminergic inhibitors, and considering the adverse outcomes of cholinergic- and monoaminergic- inhibitory therapeutics, phytoconstituents may be promising alternatives. Reports have shown that different extracts of the calyx of Hibiscus sabdariffa exhibit anticholinesterase and monoamine oxidase B inhibitory properties with the potential to delay and prevent the development of AD and PD. However, there is limited knowledge on the multitarget cholinergic and monoaminergic inhibitory activities of individual compounds in this plant. Computational methods were used to identify the specific compounds responsible for the observed cholinergic and monoaminergic inhibitory activities of the H. sabdariffa calyx extracts.

Results: Results confirm that three flavonoids: delphinidin-3-sambubioside, kaempferol-3-O-rutinoside and quercetin-3-rutinoside showed strong binding affinity with acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B while the observed stability of the ligands-enzymes complexes over the MD simulation time suggests their cholinergic and monoaminergic inhibitory properties.

Conclusion: The three flavonoids may be responsible for the reported anticholinergic and monoaminergic inhibitory potentials of H. sabdariffa extracts and could be enlisted as multi-target inhibitory agents for cholinesterases and monoamine oxidase B.

Keywords: Alzheimer’s disease, cholinesterase inhibitors, flavonoids, Hibiscus sabdariffa, Parkinson’s disease, ameliorated neuroinflammation.

Graphical Abstract
[1]
Da-Costa-Rocha, I.; Bonnlaender, B.; Sievers, H.; Pischel, I.; Heinrich, M. Hibiscus sabdariffa L. A phytochemical and pharmacological review. Food Chem., 2014, 165, 424-443.
[http://dx.doi.org/10.1016/j.foodchem.2014.05.002]
[2]
Koch, K.; Weldle, N.; Baier, S.; Büchter, C.; Wätjen, W. Hibiscus sabdariffa L. extract prolongs lifespan and protects against amyloid-β toxicity in Caenorhabditis elegans: Involvement of the FoxO and Nrf2 orthologues DAF-16 and SKN-1. Eur. J. Nutr., 2020, 59(1), 137-150.
[http://dx.doi.org/10.1007/s00394-019-01894-w]
[3]
Oboh, G.; Adewuni, T.M.; Ademiluyi, A.O.; Olasehinde, T.A.; Ademosun, A.O. Phenolic constituents and inhibitory effects of Hibiscus sabdariffa L. (Sorrel) Calyx on cholinergic, monoaminergic, and purinergic enzyme activities. J. Diet. Suppl., 2018, 15(6), 910-922.
[http://dx.doi.org/10.1080/19390211.2017.1406426] [PMID: 29341798]
[4]
Janson, B.; Prasomthong, J.; Malakul, W.; Boonsong, T.; Tunsophon, S. Hibiscus sabdariffa L. calyx extract prevents the adipogenesis of 3T3-L1 adipocytes, and obesity-related insulin resistance in high-fat diet-induced obese rats. Biomed. Pharmacother., 2021, 138, 111438.
[http://dx.doi.org/10.1016/j.biopha.2021.111438] [PMID: 33721756]
[5]
El-Shiekh, R.A.; Ashour, R.M.; Abd El-Haleim, E.A.; Ahmed, K.A.; Abdel-Sattar, E. Hibiscus sabdariffa L.: A potent natural neuroprotective agent for the prevention of streptozotocin-induced Alzheimer’s disease in mice. Biomed. Pharmacother., 2020, 128, 110303.
[http://dx.doi.org/10.1016/j.biopha.2020.110303] [PMID: 32480228]
[6]
Govindasamy, H.; Magudeeswaran, S.; Kandasamy, S.; Poomani, K. Binding mechanism of naringenin with monoamine oxidase - B enzyme: QM/MM and molecular dynamics perspective. Heliyon, 2021, 7(4), e06684.
[http://dx.doi.org/10.1016/j.heliyon.2021.e06684] [PMID: 33898820]
[7]
Alzheimer’s, A.R. Alzheimer’s disease facts and figures. Alzheimers Dement., 2019, 15(3), 321-387.
[http://dx.doi.org/10.1016/j.jalz.2019.01.010]
[8]
Chaurasiya, N.D.; Zhao, J.; Pandey, P.; Doerksen, R.J.; Muhammad, I.; Tekwani, B.L. Selective inhibition of human monoamine oxidase B by acacetin 7-methyl ether isolated from Turnera diffusa (Damiana). Molecules, 2019, 24(4), 1-15.
[http://dx.doi.org/10.3390/molecules24040810] [PMID: 30813423]
[9]
Zarotsky, V.; Sramek, J.J.; Cutler, N.R. Galantamine hydrobromide: An agent for Alzheimer’s disease. Am. J. Health Syst. Pharm., 2003, 60(5), 446-452.
[http://dx.doi.org/10.1093/ajhp/60.5.446] [PMID: 12635450]
[10]
Reiman, E.M. A 100-year update on Alzheimer’s disease and related disorders. J. Clin. Psychiatry, 2006, 67(11), 1782-1783.
[http://dx.doi.org/10.4088/JCP.v67n1117] [PMID: 17196060]
[11]
Adewole, K.E.; Ishola, A.A. BACE1 and cholinesterase inhibitory activities of compounds from Cajanus cajan and Citrus reticulata : An in silico study. In Silico Pharmacol., 2021, 9(1), 14.
[http://dx.doi.org/10.1007/s40203-020-00067-6] [PMID: 33520593]
[12]
Larit, F.; Elokely, K.M.; Chaurasiya, N.D.; Benyahia, S.; Nael, M.A.; León, F. Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants. Phytomedicine, 2018, 40, 27-36.
[13]
Bierer, L.M.; Haroutunian, V.; Gabriel, S.; Knott, P.J.; Carlin, L.S.; Purohit, D.P.; Perl, D.P.; Schmeidler, J.; Kanof, P.; Davis, K.L. Neurochemical correlates of dementia severity in Alzheimer’s disease: Relative importance of the cholinergic deficits. J. Neurochem., 1995, 64(2), 749-760.
[http://dx.doi.org/10.1046/j.1471-4159.1995.64020749.x] [PMID: 7830069]
[14]
Emamzadeh, F.N.; Surguchov, A. Parkinson’s disease: Biomarkers, treatment, and risk factors. Front. Neurosci., 2018, 12, 612.
[http://dx.doi.org/10.3389/fnins.2018.00612] [PMID: 30214392]
[15]
Shulman, J.M.; De Jager, P.L.; Feany, M.B. Parkinson’s disease: Genetics and pathogenesis. Annu. Rev. Pathol., 2011, 6(1), 193-222.
[http://dx.doi.org/10.1146/annurev-pathol-011110-130242] [PMID: 21034221]
[16]
Saki, K.; Bahmani, M.; Rafieian-Kopaei, M.; Hassanzadazar, H.; Dehghan, K.; Bahmani, F.; Asadzadeh, J. The most common native medicinal plants used for psychiatric and neurological disorders in Urmia city, northwest of Iran. Asian Pac. J. Trop. Dis., 2014, 4, S895-S901.
[http://dx.doi.org/10.1016/S2222-1808(14)60754-4]
[17]
Cheung, J.; Rudolph, M.J.; Burshteyn, F.; Cassidy, M.S.; Gary, E.N.; Love, J.; Franklin, M.C.; Height, J.J. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem., 2012, 55(22), 10282-10286.
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[18]
Rosenberry, T.L.; Brazzolotto, X.; Macdonald, I.R.; Wandhammer, M.; Trovaslet-Leroy, M.; Darvesh, S.; Nachon, F. Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study. Molecules, 2017, 22(12), 2098.
[http://dx.doi.org/10.3390/molecules22122098] [PMID: 29186056]
[19]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[20]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(10), 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[21]
Abraham, M.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1, 19-25.
[http://dx.doi.org/10.1016/j.softx.2015.06.001]
[22]
Bekker, H.; Berendsen, H.; Dijkstra, E.; Achterop, S.; Vondrumen, R.; Vanderspoel, D. Gromacs-a parallel computer for moleculardynamics simulations. 4th International Conference on Computational Physics (PC 92), 1993, pp. 252-6.
[23]
Oostenbrink, C.; Villa, A.; Mark, A.E.; van Gunsteren, W.F. A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6. J. Comput. Chem., 2004, 25(13), 1656-1676.
[http://dx.doi.org/10.1002/jcc.20090] [PMID: 15264259]
[24]
Schüttelkopf, A.W.; van Aalten, D.M. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(Pt 8), 1355-1363.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157]
[25]
Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph, 1996, 14(1), 33-38, 27-28.
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]
[26]
Kuppusamy, A.; Arumugam, M.; George, S. Combining in silico and in vitro approaches to evaluate the acetylcholinesterase inhibitory profile of some commercially available flavonoids in the management of Alzheimer’s disease. Int. J. Biol. Macromol., 2017, 95, 199-203.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.11.062] [PMID: 27871793]
[27]
Asaduzzaman, M.; Uddin, M.J.; Kader, M.A.; Alam, A.H.; Rahman, A.A.; Rashid, M.; Kato, K.; Tanaka, T.; Takeda, M.; Sadik, G. In vitro acetylcholinesterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract: Implications for the treatment of Alzheimer’s disease. Psychogeriatrics, 2014, 14(1), 1-10.
[http://dx.doi.org/10.1111/psyg.12031] [PMID: 24646308]
[28]
Ashani, Y.; Grunwald, J.; Kronman, C.; Velan, B.; Shafferman, A. Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase. Mol. Pharmacol., 1994, 45(3), 555-560.
[PMID: 8145739]
[29]
Harel, M.; Schalk, I.; Ehret-Sabatier, L.; Bouet, F.; Goeldner, M.; Hirth, C.; Axelsen, P.H.; Silman, I.; Sussman, J.L. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. USA, 1993, 90(19), 9031-9035.
[http://dx.doi.org/10.1073/pnas.90.19.9031] [PMID: 8415649]
[30]
Ordentlich, A.; Barak, D.; Kronman, C.; Flashner, Y.; Leitner, M.; Segall, Y.; Ariel, N.; Cohen, S.; Velan, B.; Shafferman, A. Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket. J. Biol. Chem., 1993, 268(23), 17083-17095.
[http://dx.doi.org/10.1016/S0021-9258(19)85305-X] [PMID: 8349597]
[31]
Darvesh, S.; Hopkins, D.A.; Geula, C. Neurobiology of butyrylcholinesterase. Nat. Rev. Neurosci., 2003, 4(2), 131-138.
[http://dx.doi.org/10.1038/nrn1035] [PMID: 12563284]
[32]
Binda, C.; Li, M.; Hubálek, F.; Restelli, N.; Edmondson, D.E.; Mattevi, A. Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc. Natl. Acad. Sci. USA, 2003, 100(17), 9750-9755.
[http://dx.doi.org/10.1073/pnas.1633804100] [PMID: 12913124]
[33]
Brühlmann, C.; Ooms, F.; Carrupt, P-A.; Testa, B.; Catto, M.; Leonetti, F.; Altomare, C.; Carotti, A. Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. J. Med. Chem., 2001, 44(19), 3195-3198.
[http://dx.doi.org/10.1021/jm010894d] [PMID: 11543689]
[34]
Cheng, X.; Ivanov, I. Molecular dynamics. Methods Mol. Biol., 2012, 929, 243-285.
[http://dx.doi.org/10.1007/978-1-62703-050-2_11] [PMID: 23007433]
[35]
Dong, Y.W.; Liao, M.L.; Meng, X.L.; Somero, G.N. Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs. Proc. Natl. Acad. Sci. USA, 2018, 115(6), 1274-1279.
[http://dx.doi.org/10.1073/pnas.1718910115] [PMID: 29358381]
[36]
Sinha, S.; Wang, S.M. Classification of VUS and unclassified variants in BRCA1 BRCT repeats by molecular dynamics simulation. Comput. Struct. Biotechnol. J., 2020, 18, 723-736.
[http://dx.doi.org/10.1016/j.csbj.2020.03.013] [PMID: 32257056]
[37]
Sogo, T.; Terahara, N.; Hisanaga, A.; Kumamoto, T.; Yamashiro, T.; Wu, S.; Sakao, K.; Hou, D.X. Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin. Biofactors, 2015, 41(1), 58-65.
[http://dx.doi.org/10.1002/biof.1201] [PMID: 25728636]
[38]
Maciel, L.G.; do Carmo, M.A.V.; Azevedo, L.; Daguer, H.; Molognoni, L.; de Almeida, M.M.; Granato, D.; Rosso, N.D. Hibiscus sabdariffa anthocyanins-rich extract: Chemical stability, in vitro antioxidant and antiproliferative activities. Food Chem. Toxicol., 2018, 113, 187-197.
[http://dx.doi.org/10.1016/j.fct.2018.01.053] [PMID: 29407472]
[39]
Xie, J.; Cui, H.; Xu, Y.; Xie, L.; Chen, W. Delphinidin-3-O-sambubioside: A novel xanthine oxidase inhibitor identified from natural anthocyanins. Food Qual Saf., 2021, 5, 1-10.
[http://dx.doi.org/10.1093/fqsafe/fyaa038]
[40]
Long, Q.; Chen, H.; Yang, W.; Yang, L.; Zhang, L. Delphinidin-3-sambubioside from Hibiscus sabdariffa. L attenuates hyperlipidemia in high fat diet-induced obese rats and oleic acid-induced steatosis in HepG2 cells. Bioengineered, 2021, 12(1), 3837-3849.
[http://dx.doi.org/10.1080/21655979.2021.1950259] [PMID: 34281481]
[41]
Hou, D.; Tong, X.; Terahara, N.; Luo, D.; Fujii, M. Delphinidin 3- sambubioside , a Hibiscus anthocyanin , induces apoptosis in human leukemia cells through reactive oxygen species-mediated mitochondrial pathway. Arch. Biochem. Biophys., 2005, 440, 101-109.
[42]
Jang, Y.S.; Wang, Z.; Lee, J-M.; Lee, J-Y.; Lim, S.S. Screening of Korean natural products for anti-adipogenesis properties and isolation of kaempferol-3-O-rutinoside as a potent anti-adipogenetic compound from Solidago virgaurea. Molecules, 2016, 21(2), 1-11.
[http://dx.doi.org/10.3390/molecules21020226] [PMID: 26901177]
[43]
Ahmad, M.; Gilani, A-H.; Aftab, K.; Ahmad, V.U. Effects of kaempferol-3-O-rutinoside on rat blood pressure. Phytother. Res., 1993, 7(4), 314-316.
[http://dx.doi.org/10.1002/ptr.2650070411]
[44]
Li, Y.; Yu, X.; Wang, Y.; Zheng, X.; Chu, Q. Kaempferol-3- O -rutinoside, a flavone derived from Tetrastigma hemsleyanum , suppresses lung adenocarcinoma via the calcium signaling pathway. Food Funct., 2021, 12(18), 8351-8365.
[http://dx.doi.org/10.1039/D1FO00581B] [PMID: 34338262]
[45]
Petpiroon, N.; Suktap, C.; Pongsamart, S.; Chanvorachote, P.; Sukrong, S. Kaempferol-3-O-rutinoside from Afgekia mahidoliae promotes keratinocyte migration through FAK and Rac1 activation. J. Nat. Med., 2015, 69(3), 340-348.
[http://dx.doi.org/10.1007/s11418-015-0899-3] [PMID: 25783411]
[46]
Habtemariam, S. A-glucosidase inhibitory activity of kaempferol-3-O-rutinoside. Nat. Prod. Commun., 2011, 6(2), 201-203.
[http://dx.doi.org/10.1177/1934578X1100600211] [PMID: 21425674]
[47]
Sachetto, A.T.A.; Rosa, J.G.; Santoro, M.L. Rutin (quercetin-3-rutinoside) modulates the hemostatic disturbances and redox imbalance induced by Bothrops jararaca snake venom in mice. PLoS Negl. Trop. Dis., 2018, 12(10), e0006774.
[http://dx.doi.org/10.1371/journal.pntd.0006774] [PMID: 30307940]
[48]
Al-Dhabi, N.A.; Arasu, M.V.; Park, C.H.; Park, S.U. An up-todate review of rutin and its biological and pharmacological activities. EXCLI J., 2015, 14, 59-63.
[49]
Xu, P.; Wang, S.; Yu, X.; Su, Y.; Wang, T.; Zhou, W. Rutin improves spatial memory in Alzheimer’s disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behav. Brain Res., 2014, 264, 173-180.
[http://dx.doi.org/10.1016/j.bbr.2014.02.002]
[50]
Zieliński, H.; Wiczkowski, W.; Honke, J.; Piskuła, M.K. In vitro expanded bioaccessibility of quercetin-3-rutinoside and quercetin aglycone from buckwheat biscuits formulated from flours fermented by lactic acid bacteria. Antioxidants, 2021, 10(4), 571.
[http://dx.doi.org/10.3390/antiox10040571] [PMID: 33917795]
[51]
Sun, X.; Li, L.; Dong, Q.X.; Zhu, J.; Huang, Y.; Hou, S. Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J. Neuroinflammation, 2021, 18(1), 1-14.
[52]
Choi, J.Y.; Lee, J.M.; Lee, D.G.; Cho, S.; Yoon, Y.H.; Cho, E.J.; Lee, S. The n-butanol fraction and rutin from tartary buckwheat improve cognition and memory in an in vivo model of amyloid-β-induced alzheimer’s disease. J. Med. Food, 2015, 18(6), 631-641.
[http://dx.doi.org/10.1089/jmf.2014.3292] [PMID: 25785882]
[53]
Gupta, R.; Singh, M.; Sharma, A. Neuroprotective effect of antioxidants on ischaemia and reperfusion-induced cerebral injury. Pharmacol. Res., 2003, 48(2), 209-215.
[http://dx.doi.org/10.1016/S1043-6618(03)00102-6] [PMID: 12798674]
[54]
Pu, F.; Mishima, K.; Irie, K.; Motohashi, K.; Tanaka, Y.; Orito, K.; Egawa, T.; Kitamura, Y.; Egashira, N.; Iwasaki, K.; Fujiwara, M. Neuroprotective effects of quercetin and rutin on spatial memory impairment in an 8-arm radial maze task and neuronal death induced by repeated cerebral ischemia in rats. J. Pharmacol. Sci., 2007, 104(4), 329-334.
[http://dx.doi.org/10.1254/jphs.FP0070247] [PMID: 17666865]
[55]
Javed, H.; Khan, M.M.; Ahmad, A.; Vaibhav, K.; Ahmad, M.E.; Khan, A.; Ashafaq, M.; Islam, F.; Siddiqui, M.S.; Safhi, M.M.; Islam, F. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience, 2012, 210, 340-352.
[http://dx.doi.org/10.1016/j.neuroscience.2012.02.046] [PMID: 22441036]
[56]
Dzoyem, J.P.; Nkuete, A.H.; Ngameni, B.; Eloff, J.N. Antiinflammatory and anticholinesterase activity of six flavonoids isolated from Polygonum and Dorstenia species. Arch. Pharm. Res., 2017, 40(10), 1129-1134.
[PMID: 26048035]
[57]
Khan, M.T.H.; Orhan, I.; Şenol, F.S.; Kartal, M.; Şener, B.; Dvorská, M.; Smejkal, K.; Slapetová, T. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem. Biol. Interact., 2009, 181(3), 383-389.
[http://dx.doi.org/10.1016/j.cbi.2009.06.024] [PMID: 19596285]

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