In Silico Screening and DFT Analysis of Nelumbo nucifera Phytochemicals as Potential BACE-1 Inhibitors for Alzheimer’s disease
DOI:
https://doi.org/10.56782/pps.379Keywords:
Alzheimer, Nelumbo nucifera, β-secretase, In Silico, Docking and DFT analysisAbstract
Alzheimer's disease (AD) stands as one of the primary neurological disorders affecting humans. This condition is marked by deterioration of central nervous system function. The enzyme β-secretase (BACE-1) plays a crucial part in AD pathogenesis by initiating the destruction of the amyloid precursor protein (APP). Consequently, BACE-1 has become a significant focus for therapeutic interventions in AD. Nelumbo nucifera phytochemical structures have been virtually scrutinized for the expansion of potent and selective therapeutic compounds. In silico analysis of 24 different phytochemical structures from Nelumbo nucifera have been carried out against the BACE-1 to explore the anti-Alzheimer potential. Anonaine, asimilobine, dehydroanonaine, liriodenine, and roemerin were found to be prominently binding with BACE-1 and found to be more stable in DFT analysis, which indicated physicochemical exploration of the Nelumbo nucifera may result in potent and selective anti-Alzheimer agents.
Downloads
References
1. Cummings, J.; Zhou, Y.; Lee, G.; Zhong, K.; Fonseca, J.; Cheng, F. Alzheimer’s disease drug development pipeline: 2024. Alzheimers Dement. (NY). 2024, 10(2), Art. No: e12465. DOI: 10.1002/trc2.12465 DOI: https://doi.org/10.1002/trc2.12465
2. Potbhare, M.S.; Barik, R.; Khobragade, D.S. Management of Alzheimer’s Disease : A Review of Herbal Drugs Having Potential Pharmacological and Therapeutic Activity. J. Young Pharm. 2023, 15(1), 13-30. DOI: 10.5530/097515050344 DOI: https://doi.org/10.5530/097515050344
3. Temviriyanukul, P.; Sritalahareuthai, V.; Promyos, N.; Thangsiri, S.; Pruesapan, K.; Srinuanchai, W.; Nuchuchua, O.; Siriwan, D.; On-nom, N.; Suttisansanee, U. The Effect of Sacred Lotus (Nelumbo nucifera) and Its Mixtures on Phenolic Profiles, Antioxidant Activities, and Inhibitions of the Key Enzymes Relevant to Alzheimer’s Disease. Molecules 2020, 25(16), Art. No: 3713. DOI: 10.3390/molecules25163713
4. Khan, S.; Khan, H.U.; Khan, F.A.; Shah, A.;Wadood, A.; Ahmad, S.; Almehmadi, M.; Alsaiari, A.A.; Shah, F.U.; Kamran, N. Anti-Alzheimer and Antioxidant Effects of Nelumbo nucifera L. Alkaloids, Nuciferine and Norcoclaurine in Alloxan-Induced Diabetic Albino Rats. Pharmaceuticals 2022, 15(10), Art. No: 1205. DOI: 10.3390/ph15101205 DOI: https://doi.org/10.3390/ph15101205
5. Mitra, K.; Raihan, M.A.; Rahman, M.A.; Rouf, R.; Reza, H.M.; Shaikh, J.U.; Muhammad, I. Therapeutic Potential of Nelumbo nucifera (Sacred Lotus) in CNS Disorders. Dhaka Univ. J. Pharm. Sci. 2021, 20(3), 347 358. DOI: 10.3329/dujps.v20i3.59800 DOI: https://doi.org/10.3329/dujps.v20i3.59800
6. Divakaran, D.; Sriariyanun, M.; Suyambulingam, I.; Mavinkere Rangappa, S.; Siengchin, S. Exfoliation and physico-chemical characterization of novel bioplasticizers from Nelumbo nucifera leaf for biofilm application. Heliyon 2023, 9(12), Art. No: e22550. DOI: 10.1016/j.heliyon.2023.e22550 DOI: https://doi.org/10.1016/j.heliyon.2023.e22550
7. Xu, H.; Wang, C.; Gong, L. Hypoglycemic activity in vivo and in vitro of the Lotus (Nelumbo nucifera Gaertn.) seed skin (testa) phenolic-rich extracts. Food Chem. X. 2024, 22, Art. No: 101282. DOI: 10.1016/j.fochx.2024.101282 DOI: https://doi.org/10.1016/j.fochx.2024.101282
8. Kumaran, A.; Ho, C.C.; Hwang, L.S. Protective effect of Nelumbo nucifera extracts on beta amyloid protein induced apoptosis in PC12 cells, in vitro model of Alzheimer’s disease. J. Food Drug Anal. 2018, 26(1), 172-181. DOI: 10.1016/j.jfda.2017.01.007 DOI: https://doi.org/10.1016/j.jfda.2017.01.007
9. Ahn, J.H.; Kim, E.S.; Lee, C. Chemical constituents from Nelumbo nucifera leaves and their anti-obesity effects. Bioorganic Med. Chem. Lett. 2013, 23(12), 3604-3608. DOI: 10.1016/j.bmcl.2013.04.013 DOI: https://doi.org/10.1016/j.bmcl.2013.04.013
10. Cho, E.J.; Yokozawa, T.; Rhyu, D.Y.; Kim, H.Y.; Shibahara, N.; Park, J.C. The inhibitory effects of 12 medicinal plants and their component compounds on lipid peroxidation. Am. J. Chin. Med. 2003, 31(6), 907-917. DOI: 10.1142/S0192415X03001648 DOI: https://doi.org/10.1142/S0192415X03001648
11. Hu, P.; Ge, X.; Gao, M.; Wang, X.; Zhang, Y.; Li, Y. Nelumbo nucifera Gaertn: An updated review of the antitumor activity and mechanisms of alkaloids. Pharmacol. Res. Mod. Chin. Med. 2022, 5, Art. No: 100167. DOI: 10.1016/j.prmcm.2022.100167 DOI: https://doi.org/10.1016/j.prmcm.2022.100167
12. Huang, C.F.; Chen, Y.W.; Yang, C.Y.; Lin, H.Y.; Way, T.D.; Chiang, W. Extract of lotus leaf (Nelumbo nucifera) and its active constituent catechin with insulin secretagogue activity. J. Agric. Food Chem. 2011, 59(4), 1087-1094. DOI: 10.1021/jf103382h DOI: https://doi.org/10.1021/jf103382h
13. Jiang, X.L.; Wang, L.; Wang, E.J.; Zhang, G.L.; Chen, B.; Wang, M.K. Flavonoid glycosides and alkaloids from the embryos of Nelumbo nucifera seeds and their antioxidant activity. Fitoterapia 2018, 125, 184-190. DOI: 10.1016/j.fitote.2018.01.009 DOI: https://doi.org/10.1016/j.fitote.2018.01.009
14. Kashiwada, Y.; Aoshima, A.; Ikeshiro, Y.; Chen, Y.P.; Furukawa, H.; Itoigawa, M. Anti HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids. Bioorg. Med. Chem. 2005, 13, 443 448. DOI: 10.1016/j.bmc.2004.10.020 DOI: https://doi.org/10.1016/j.bmc.2004.10.020
15. Kaur, P.; Kaur, L.; Kaur, N.; Singh, A. A brief review on pharmaceutical uses of Nelumbo nucifera. J. Pharmacogn. Phytochem. 2019, 8(3), 3966-3972.
16. Ki, H.K.; Sang, W.C.; Shi, Y.R.; San, U.C.; Kang, R.L. Phytochemical constituents of Nelumbo nucifera. Nat. Prod. Sci. 2009, 15(2), 90-95.
17. Lin, H.Y.; Kuo, Y.H.; Lin, Y.L.; Chiang, W. Antioxidative effect and active components from leaves of lotus (Nelumbo nucifera). J. Agric. Food Chem. 2009, 57, 6623-6629. DOI: 10.1021/jf900950z DOI: https://doi.org/10.1021/jf900950z
18. Liu, S.; Li, D.; Huang, B.; Chen, Y.; Lu, X.; Wang, Y. Inhibition of pancreatic lipase, α-glucosidase, α-amylase, and hypolipidemic effects of the total flavonoids from Nelumbo nucifera leaves. J. Ethnopharmacol. 2013, 149, 263-269. DOI: 10.1016/j.jep.2013.06.034 DOI: https://doi.org/10.1016/j.jep.2013.06.034
19. Mukherjee, P.K.; Mukherjee, D.; Maji, A.K.; Rai, S.; Heinrich, M. The sacred lotus (Nelumbo nucifera) - phytochemical and therapeutic profile. J. Pharm. Pharmacol. 2009, 61, 407 422. DOI: 10.1211/jpp/61.04.0001 DOI: https://doi.org/10.1211/jpp/61.04.0001
20. Ono, Y.; Hattori, E.; Fukaya, Y.; Imai, S.; Ohizumi, Y. Anti-obesity effect of Nelumbo nucifera leaves extract in mice and rats. J. Ethnopharmacol. 2006, 106, 238 244. DOI: 10.1016/j.jep.2005.12.036 DOI: https://doi.org/10.1016/j.jep.2005.12.036
21. Paudel, K.R.; Panth, N. Phytochemical profile and biological activity of Nelumbo nucifera. Evid.-based Complement. Altern Med. 2015, 2015, Art. No: 789124. DOI: 10.1155/2015/789124 DOI: https://doi.org/10.1155/2015/789124
22. Temviriyanukul, P.;Sritalahareuthai, V.; Promyos, N.; Thangsiri, S.;Pruesapan, K.;Srinuanchai, W. The Effect of Sacred Lotus (Nelumbo nucifera) and Its Mixtures on Phenolic Profiles, Antioxidant Activities, and Inhibitions of the Key Enzymes Relevant to Alzheimer’s Disease. Molecules 2020, 25(16), Art. No: 3713. DOI: 10.3390/molecules25163713 DOI: https://doi.org/10.3390/molecules25163713
23. Wang, H.M.; Yang, W.L.; Yang, S.C.; Chen, C.Y. Chemical constituents from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena. Chem. Nat. Compd. 2011, 47, 316-318. DOI: 10.1007/s10600-011-9919-z DOI: https://doi.org/10.1007/s10600-011-9919-z
24. Wen, Y.P.; Fu, H.J.; Chen, Q.; Lan, C.; Qin, D.L.; Wu, J.M. Exploring the therapeutic potential of Nelumbo nucifera leaf extract against amyloid-beta-induced toxicity in the Caenorhabditis elegans model of Alzheimer’s disease. Front. Pharmacol. 2024, 15, Art. No: 1408031. DOI: 10.3389/fphar.2024.1408031 DOI: https://doi.org/10.3389/fphar.2024.1408031
25. Wu, C.H.; Yang, M.Y.; Chan, K.C.; Chung, P.J.;Ou, T.T.; Wang, C.J. Improvement in high-fat diet-induced obesity and body fat accumulation by a Nelumbo nucifera leaf flavonoid-rich extract in mice. J. Agric. Food Chem. 2010, 58, 7075-7081. DOI: 10.1021/jf101415v DOI: https://doi.org/10.1021/jf101415v
26. Zhang, Y.; Xu, Y.; Wang, Q.; Zhang, J.; Dai, X.; Miao, S. The antioxidant capacity and nutrient composition characteristics of lotus (Nelumbo nucifera Gaertn.) seed juice and their relationship with color at different storage temperatures. Food Chem. X. 2023, 18, Art. No: 100669. DOI:10.1016/j.fochx.2023.100669 DOI: https://doi.org/10.1016/j.fochx.2023.100669
27. DassaultSystèmes, BIOVIA Discovery Studio Visualizer, (2020).
28. Crystal structure of BACE1 in complex with 2-aminooxazoline 3 azaxanthene inhibitor 2. Available online: https://www.rcsb.org/structure/5i3w (accessed on 30 August 2023).
29. Dallakyan, S.; Olson, A.J. Small-Molecule Library Screening by Docking with PyRx. Methods Mol. Biol. 2015, 1263, 243-50. DOI:10.1007/978-1-4939-2269-7_19 DOI: https://doi.org/10.1007/978-1-4939-2269-7_19
30. Jordan, J.B.; Whittington, D.A.; Bartberger, M.D.; Sickmier, E.A.; Chen, K.; Cheng, Y. Fragment-Linking Approach Using 19F NMR Spectroscopy to Obtain Highly Potent and Selective Inhibitors of β-Secretase. J. Med. Chem. 2016, 59, 3732 3749. DOI: 10.1021/acs.jmedchem.5b01917 DOI: https://doi.org/10.1021/acs.jmedchem.5b01917
31. Daina, A., Michielin, O., Zoete, V. Swiss ADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, Art. No: 42717. DOI: 10.1038/srep42717 DOI: https://doi.org/10.1038/srep42717
32. Walsh, E.J. ACD/ChemSketch 1.0 (freeware); ACD/ChemSketch 2.0 and its Tautomers, Dictionary, and 3D Plug ins; ACD/HNMR 2.0; ACD/CNMR 2.0, J. Chem. Educ. 1997, 74. DOI: 10.1021/ed074p905 DOI: https://doi.org/10.1021/ed074p905
33. Rochlani, S.; Bhatia, M.; Rathod, S.; Choudhari, P; Dhavale, R. Exploration of limonoids for their broad spectrum antiviral potential via DFT, molecular docking and molecular dynamics simulation approach. Nat. Prod. Res. 2023, 38(5), 891 896. DOI: 10.1080/14786419.2023.2202398 DOI: https://doi.org/10.1080/14786419.2023.2202398
34. Bakale, R.D.; Phatak, P.S.; Rathod, S.S.; Choudhari, P.B.; Rekha, E.M. In vitro and in silico exploration of newly synthesized triazolyl isonicotinohydrazides as potent antitubercular agents. J. Biomol. Struct. Dyn. 2023, 1372 1391. DOI: 10.1080/07391102.2023.2291826 DOI: https://doi.org/10.1080/07391102.2023.2291826
35. Rathod, S.; Bhande, D.; Pawar, S.; Gumphalwad, K.; Choudhari, P.; More, H. Identification of Potential Hits against Fungal Lysine Deacetylase Rpd3 via Molecular Docking, Molecular Dynamics Simulation, DFT, In-Silico ADMET and Drug Likeness Assessment. Chem. Afr. 2023, 7, 1151–1164. DOI: 10.1007/s42250-023-00766-5 DOI: https://doi.org/10.1007/s42250-023-00766-5
36. Bursch, M.; Mewes, J.M.; Hansen, A.; Grimme, S. Best-Practice DFT Protocols for Basic Molecular Computational Chemistry. Angew. Chem., Int. Ed. 2022, 61(42), Art. No: e202205735. DOI: 10.1002/anie.202205735 DOI: https://doi.org/10.1002/anie.202205735
37. Jensen F. Atomic orbital basis sets. WIREs Comput. Mol. Sci. 2013, 33, 273–295. DOI: 10.1002/wcms.1123 DOI: https://doi.org/10.1002/wcms.1123
38. Mardirossian, N.; Head-Gordon, M. Thirty years of density functional theory in computational chemistry: an overview and extensive assessment of 200 density functionals. Mol. Phys. 2017, 115, 2315 2372. DOI: 10.1080/00268976.2017.1333644 DOI: https://doi.org/10.1080/00268976.2017.1333644
39. Piela, L. Chasing the Correlation Dragon: Density Functional Theory (DFT). In Ideas of Quantum Chemistry, 3rd ed.; Piela, L., Ed.; Elsevier: Amsterdam, Netherlands, 2020; 1, pp. 191–252. DOI: 10.1016/B978-0-44-464248-6.00011-9 DOI: https://doi.org/10.1016/B978-0-44-464248-6.00011-9
40. Tirado-Rives, J.; Jorgensen, W.L. Performance of B3LYP density functional methods for a large set of organic molecules. J. Chem. Theory Comput. 2008, 4(2), 297 306. DOI: 10.1021/ct700248k DOI: https://doi.org/10.1021/ct700248k
41. Neese, F. Software update: The ORCA program system—Version 5.0. WIREs Comput. Mol. Sci. 2022, 12(5), Art. No: e1606. DOI: 10.1002/WCMS.1606 DOI: https://doi.org/10.1002/wcms.1606
42. Neese, F.; Wennmohs, F.; Becker, U.; Riplinger, C. The ORCA quantum chemistry program package. J. Chem. Phys. 2020, 152, Art. No: 224108. DOI: 10.1063/5.0004608. DOI: https://doi.org/10.1063/5.0004608
43. Snyder, H.D.; Kucukkal, T.G. Computational Chemistry Activities with Avogadro and ORCA. J. Chem. Educ. 2021, 98, 1335 1341. DOI: 10.1021/acs.jchemed.0c00959 DOI: https://doi.org/10.1021/acs.jchemed.0c00959
44. Rathod, S.; Shinde, S.; Choudhari, P.; Sarkate, A.; Chaudhari, S.; Shingan, A. Exploring binding potential of two new indole alkaloids from Nauclea officinalis against third and fourth generation EGFR: druglikeness, in silico ADMET, docking, DFT, molecular dynamics simulation, and MMGBSA study. Nat. Prod. Res. 2025, 39(10), 2970-2977. DOI: 10.1080/14786419.2023.2301678 DOI: https://doi.org/10.1080/14786419.2023.2301678
45. Kilbile, J.T.; Tamboli, Y.; Ansari, S.A.; Rathod, S.S.; Choudhari, P.B.; Alkahtani, H.; Sapkal, S.B. Synthesis, Biological Evaluation, and Computational Studies of 6 Fluoro 3 (Piperidin 4 yl) 1,2 Benzisoxazole Sulfonamide Conjugates. Polycycl. Aromat. Compd. 2023, 44(6), 4157 177. DOI: 10.1080/10406638.2023.2247117 DOI: https://doi.org/10.1080/10406638.2023.2247117
46. Puthanveedu, V.; Muraleedharan, K.Phytochemicals as potential inhibitors for COVID-19 revealed by molecular docking, molecular dynamic simulation and DFT studies. Struct. Chem.2022, 33, 1423 1443. DOI: 10.1007/s11224 022 01982-4 DOI: https://doi.org/10.1007/s11224-022-01982-4
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Rohit Todkar, Pramodkumar Shirote, Shrinivas Mohite
This work is licensed under a Creative Commons Attribution 4.0 International License.
For all articles published in Prospects in Pharmaceutical Sciences copyright is retained by the authors. The journal publishes articles in the Open Access policy, within the CC BY 4.0 licence.
This is a human-readable summary of (and not a substitute for) the license. Disclaimer.
You are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material for any purpose, even commercially.
The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Notices:
You do not have to comply with the license for elements of the material in the public domain or where your use is permitted by an applicable exception or limitation.
No warranties are given. The license may not give you all of the permissions necessary for your intended use. For example, other rights such as publicity, privacy, or moral rights may limit how you use the material.
How to Cite
