Skip to main content

Advertisement

SpringerLink
Log in

Unravelling the Untapped Pharmacological Potential of Plant Molecules as Inhibitors of BACE1: In Silico Explorations for Alzheimer’s Disease

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is an extremely complex, heterogeneous, and multifactorial neurodegenerative disease clinically characterized by progressive memory loss and progressive decline in cognitive function. There is currently no effective treatment for the onset and/or progression of the pathophysiological diseases of AD. The global prevalence of this disease has increased in recent years due to modern lifestyle. Therefore, there is an urgent need to develop a drug with significant neuroprotective potential. Since plant metabolites, especially polyphenols, have important pharmacological properties acting against β-amyloid (Aβ), Tau, neuroinflammation, and oxidative stress, such phytochemicals were selected in the present research. Using the Schrödinger tool (Maestro V.13.6), the drug potency of these metabolites was studied after installation in the highly configured workstation. Among the 120 polyphenols docked, amygdalin showed notable docking values of − 11.2638, followed by eriocitrin (− 10.9569), keracyanin (− 10.7086), and amaroswerin (− 9.48126). The prominent MM-GBSA values of these molecules were − 62.8829, − 52.1914, − 68.6307, and − 63.1074, respectively. The MM-GBSA energy values demonstrated the drug stability of these molecules for β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)-causing AD. In the absorption and distribution assessment, these phytochemicals showed significantly better values than the inhibitors CNP520. The chosen phytochemicals have been demonstrated as non-hepatotoxic; however, the BACE1 inhibitor CNP520 is hepatotoxic. In both the molecular docking and ADMET assessments, these natural chemicals have shown optimism as potential drug candidates for Alzheimer’s disease. However, in order to understand the detailed biological metabolism of these compounds in AD, they need to be evaluated in in vivo studies to validate its efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2 
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

Data Availability

Data will be shared based on the request.

References

  1. ADI. (2022). Alzheimer’s disease international report. https://www.alzint.org/about/. Accessed on 2.07.2023

  2. Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015). Alzheimer’s disease. Nature Reviews Drug Discovery Primers, 1, 1–18. https://doi.org/10.1038/nrdp.2015.56

    Article  Google Scholar 

  3. Golde, T. E., Dickson, D., & Hutton, M. (2006). Filling the gaps in the abeta cascade hypothesis of Alzheimer’s disease. Current Alzheimer Research, 3(5), 421–430. https://doi.org/10.2174/156720506779025189

    Article  PubMed  CAS  Google Scholar 

  4. Cole, S. L., & Vassar, R. (2007). The Alzheimer’s disease beta-secretase enzyme, BACE1. Molecular Neurodegeneration, 15(2), 22. https://doi.org/10.1186/1750-1326-2-22

    Article  CAS  Google Scholar 

  5. De Strooper, B., Iwatsubo, T., & Wolfe, M. S. (2012). Presenilins and γ-secretase: Structure, function, and role in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 2, a006304. https://doi.org/10.1101/cshperspect.a006304

    Article  PubMed  PubMed Central  Google Scholar 

  6. Janelidze, S., Zetterberg, H., Mattsson, N., Palmqvist, S., Vanderstichele, H., Lindberg, O., Westen, D., Stomrud, E., Minthon, L., Blennow, K., & Hansson, O. (2016). CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: Better diagnostic markers of Alzheimer disease. Annals of Clinical Translational Neurology, 3(3), 154–165. https://doi.org/10.1002/acn3.274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Koelsch, G. (2017). BACE1 Function and inhibition: Implications of intervention in the amyloid pathway of Alzheimer’s disease pathology. Molecules, 22(10), 1723. https://doi.org/10.3390/molecules22101723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Mullard, A. (2017). BACE inhibitor bust in Alzheimer trial. Nature Reviews Drug Discovery, 16, 155.

    PubMed  Google Scholar 

  9. Wightman, E. (2017). Potential benefits of phytochemicals against Alzheimer’s disease. The Proceedings of the Nutrition Society, 76(2), 106–112. https://doi.org/10.1017/S0029665116002962

    Article  PubMed  Google Scholar 

  10. Coimbra, J. R. M., Marques, D. F. F., Baptista, S. J., Pereira, C. M. F., Moreira, P. I., Dinis, T. C. P., Santos, A. E., & Salvador, J. A. R. (2018). Highlights in BACE1 inhibitors for Alzheimer’s disease treatment. Frontiers in Chemistry, 24(6), 178. https://doi.org/10.3389/fchem.2018.00178

    Article  CAS  Google Scholar 

  11. Sajad, M., Kumar, R., & Thakur, S. C. (2022). History in perspective: The prime pathological players and role of phytochemicals in Alzheimer’s disease. IBRO Neuroscience Reports, 28(12), 377–389. https://doi.org/10.1016/j.ibneur.2022.04.009

    Article  CAS  Google Scholar 

  12. Rani, M. J., & J., Kalaimathi, K., Vijayakumar, S., Varatharaju, G., Karthikeyan, K., Thiyagarajan, G., Bhavani, K., Manogar, P., & Prabhu, S. (2022). Anti-viral effectuality of plant polyphenols against mutated dengue protein NS2B47-NS3: A computational exploration. Gene Reports, 27. https://doi.org/10.1016/j.genrep.2022.101546

  13. Wang, X., Kim, J. R., Lee, S. B., Kim, Y. J., Jung, M. Y., Kwon, H. W., & Ahn, Y. J. (2014). Effects of curcuminoids identified in rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer’s disease drosophila models.

    Book  Google Scholar 

  14. Cox, C. J., Choudhry, F., Peacey, E., Perkinton, M. S., Richardson, J. C., Howlett, D. R., Lichtenthaler, S. F., Francis, P. T., & Williams, R. J. (2015). Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing. Neurobiology of Aging, 36, 178–187. https://doi.org/10.1016/j.neurobiolaging.2014.07.032

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Guo, Y., Zhao, Y., Nan, Y., Wang, X., Chen, Y., & Wang, S. (2017). (-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer’s disease. NeuroReport, 28, 590–597. https://doi.org/10.1097/WNR.0000000000000803

    Article  PubMed  CAS  Google Scholar 

  16. Gaamouch, F., Chen, F., Ho, L., Lin, H. Y., Yuan, C., Wong, J., & Wang, J. (2022). Benefits of dietary polyphenols in Alzheimer’s disease. Frontiers in Aging Neuroscience, 13(14), 1019942. https://doi.org/10.3389/fnagi.2022

    Article  Google Scholar 

  17. Moertel, C. G., Fleming, T. R., Rubin, J., Kvols, L. K., Sarna, G., Koch, R., Currie, V. E., Young, C. W., Jones, S. E., & Davignon, J. P. (1982). A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. New England Journal of Medicine, 306(4), 201–206. https://doi.org/10.1056/NEJM198201283060403

    Article  PubMed  CAS  Google Scholar 

  18. Swain, E., & Poulton, J. E. (1994). Utilization of amygdalin during seedling development of Prunus serotina. Plant Physiology, 106(2), 437–445. https://doi.org/10.1104/pp.106.2.437

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bolarinwa, I. F., Orfila, C., & Morgan, M. R. (2014). Amygdalin content of seeds, kernels and food products commercially available in the UK. Food Chemistry, 152, 133–139. https://doi.org/10.1016/j.foodchem.2013.11.002

    Article  PubMed  CAS  Google Scholar 

  20. Barceloux, D. G. (2009). Cyanogenic foods (cassava, fruit kernels, and cycad seeds). Disease-a-Month, 55(6), 336–352. https://doi.org/10.1016/j.disamonth.2009.03.010

    Article  PubMed  Google Scholar 

  21. Yang, H. Y., Chang, H. K., Lee, J. W., Kim, Y. S., Kim, H., Lee, M. H., Shin, M. S., Ham, D. H., Park, H. K., Lee, H., & Kim, C. J. (2007). Amygdalin suppresses lipopolysaccharide-induced expressions of cyclooxygenase-2 and inducible nitric oxide synthase in mouse BV2 microglial cells. Neurological Research, 29(1), 59–S64. https://doi.org/10.1179/016164107X172248

    Article  Google Scholar 

  22. Jiagang, D., Li, C., Wang, H., Hao, E., Du, Z., Bao, C., Lv, J., & Wang, Y. (2011). Amygdalin mediates relieved atherosclerosis in apolipoprotein E deficient mice through the induction of regulatory T cells. Biochemical and Biophysical Research Communications, 411(3), 523–529. https://doi.org/10.1016/j.bbrc.2011.06.162

    Article  PubMed  CAS  Google Scholar 

  23. Taiwo, I. A., Odeigah, P. G. C., Jaja, S., & Mojiminiyi, F. (2010). Cardiovascular effects of Vernonia amygdalina in rats and the implications for treatment of hypertension in diabetes. Researcher, 2, 76–79.

    Google Scholar 

  24. Yang, C., Zhao, J., Cheng, Y., Li, X., & Rong, J. (2014). Bioactivity-guided fractionation identifies amygdalin as a potent neurotrophic agent from herbal medicine Semen Persicae extract. Biomed Research International, 306857. https://doi.org/10.1155/2014/306857

  25. Vahedi-Mazdabadi, Y., Karimpour-Razkenari, E., Akbarzadeh, T., Lotfian, H., Toushih, M., Roshanravan, N., Saeedi, M., & Ostadrahimi, A. (2020). Anti-cholinesterase and neuroprotective activities of sweet and bitter apricot kernels (Prunus armeniaca L). Iranian Journal Pharmaceutical Research: IJPR, 19(4), 216. https://doi.org/10.22037/2Fijpr.2019.15514.13139

    Article  PubMed Central  CAS  Google Scholar 

  26. Moslehi, A., Komeili-Movahed, T., & Moslehi, M. (2019). Antioxidant effects of amygdalin on tunicamycin-induced endoplasmic reticulum stress in the mice liver: Cross talk between endoplasmic reticulum stress and oxidative stress. Journal of Reports in Pharmaceutical Sciences, 8, 298–302. https://doi.org/10.4103/jrptps.JRPTPS_35_19

    Article  CAS  Google Scholar 

  27. Jaswal, V., & Palanivelu, J. C. R. (2018). Effects of the gut microbiota on amygdalin and its use as an anti-cancer therapy: Substantial review on the key components involved in altering dose efficacy and toxicity. Biochemistry and Biophysics Reports, 14, 125–132. https://doi.org/10.1016/j.bbrep.2018.04.008

    Article  PubMed  PubMed Central  Google Scholar 

  28. Song, Z., & Xu, X. (2014). Advanced research on anti-tumor effects of amygdalin. Journal of Cancer Research and Therapeutics, 10, 3–7. https://doi.org/10.4103/0973-1482.139743

    Article  PubMed  CAS  Google Scholar 

  29. Oduwole, I., & Abdelnaser, A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 039–049. https://doi.org/10.26502/jbb.2642-91280026

    Article  Google Scholar 

  30. Blaheta, R. A., Nelson, K., Haferkamp, A., & Juengel, E. (2016). Amygdalin, quackery or cure? Phytomedicine, 23, 367–376. https://doi.org/10.1016/j.phymed.2016.02.004

    Article  PubMed  CAS  Google Scholar 

  31. Coates, M. E., & Walker, R. (1992). Interrelationships between the gastrointestinal microflora and nonnutrient components of the diet. Nutrition Research Reviews, 5, 85–96. https://doi.org/10.1079/NRR19920008

    Article  PubMed  CAS  Google Scholar 

  32. Miyake, Y., Suzuki, E., Ohya, S., Fukumoto, S., Hiramitsu, M., Sakaida, K., Osawa, T., & Furuichi, Y. (2006). Lipid-lowering effect of eriocitrin, the main flavonoid in lemon fruit, in rats on a highfat and high-cholesterol diet. Journal of Food Science, 71(9), 633–637. https://doi.org/10.1111/j.1750-3841.2006.00192.x

    Article  CAS  Google Scholar 

  33. Nogata, Y., Ohta, H., Ishii, T., & Sekiya, K. (2007). Isolation of eriocitrin (eriodictyol 7-Orutinoside) as an arachidonate lipoxygenase inhibitor from Lumie fruit (Citrus lumia) and its distribution in Citrus species. Journal of the Science of Food and Agriculture, 87(1), 82–89. https://doi.org/10.1002/jsfa.2674

    Article  CAS  Google Scholar 

  34. Miyake, Y., Yamamoto, K., & Osawa, T. (1997). Isolation of eriocitrin (eriodictyol 7-rutinoside) from lemon fruit (Citrus limon BURM. f.) and its antioxidative activity. Food Science and Technology International, 3(1), 84–88. https://doi.org/10.3136/fsti9596t9798.3.84

    Article  CAS  Google Scholar 

  35. Kwon, E. Y., & Choi, M. S. (2020). Eriocitrin improves adiposity and related metabolic disorders in high-fat diet-induced obese mice. Journal of Medicinal Food, 23(3), 233–241. https://doi.org/10.1089/jmf.2019.4638

    Article  PubMed  CAS  Google Scholar 

  36. Gangadhariah, M., Pardhi, T., Ravilla, J., Chandra, S., & Singh, S. A. (2022). Citrus nutraceutical eriocitrin and its metabolites are partial agonists of peroxisome proliferator-activated receptor gamma (PPARγ): A molecular docking and molecular dynamics study. Journal of Biomolecular Structure &Dynamics, 28, 1–21. https://doi.org/10.1080/07391102.2022.2162127

    Article  CAS  Google Scholar 

  37. Yao, L., Liu, W., Bashir, M., Nisar, M. F., & Wan, C. C. (2022). Eriocitrin: A review of pharmacological effects. Biomedicine & Pharmacotherapy, 154, 113563. https://doi.org/10.1016/j.biopha.2022.113563

    Article  CAS  Google Scholar 

  38. Yuan, Z., Zhu, M., Wei, X., & Li, X. (2023). Eriocitrin alleviates sevoflurane-induced cytotoxicity in HT22 cells via Nrf2 pathway. Tropical Journal Pharmaceutical Research, 22(2), 259–264. https://doi.org/10.4314/tjpr.v21i2.7

    Article  CAS  Google Scholar 

  39. He, J., Zhou, D., & Yan, B. (2020). Eriocitrin alleviates oxidative stress and inflammatory response in cerebral ischemia reperfusion rats by regulating phosphorylation levels of Nrf2/NQO-1/HO-1/NF-κB p65 proteins. Annals of Translational Medicine, 8(12), 757. https://doi.org/10.21037/2Fatm-20-4258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Xu, J., Ma, I., & Fu, P. (2021). Eriocitrin attenuates ischemia reperfusion-induced oxidative stress and inflammation in rats with acute kidney injury by regulating the dualspecificity phosphatase 14 (DUSP14)-mediated Nrf2 and nuclear factor-κB (NF-κB) pathways. Annals Translation of Medicine, 9(4):350. https://doi.org/10.21037/2Fatm-21-337

    Article  CAS  Google Scholar 

  41. Duan, X., Hao, Y., Liang, X., Qiu, G., & Xue, W. (2021). Eriocitrin alleviates the arterial occlusionmediated cerebral ischemic-reperfusion injury through the modulation of apoptotic proteins and immune markers in mice. Pharmacognosy Magazine, 17(73), 193–199. https://doi.org/10.4103/pm.pm_577_19

    Article  CAS  Google Scholar 

  42. Bassolino, L., Fulvio, F., Pastore, C., Pasini, F., GallinaToschi, T., Filippetti, I., & Paris, R. (2023). When Cannabis sativa L. turns purple: Biosynthesis and accumulation of anthocyanins. Antioxidants, 12, 1393. https://doi.org/10.3390/antiox12071393

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Temviriyanukul, P., Sritalahareuthai, V., Jom, K. N., Jongruaysup, B., Tabtimsri, S., Pruesapan, K., Thangsiri, S., Inthachat, W., Siriwan, D., Charoenkiatkul, S., & Suttisansanee, U. (2020). Comparison of phytochemicals, antioxidant, and in vitro anti-Alzheimer properties of twenty-seven Morus spp cultivated in Thailand. Molecules, 25(11), 2600. https://doi.org/10.3390/molecules25112600

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wu, T., Qi, X., Liu, Y., Guo, J., Zhu, R., Chen, W., Zheng, X., & Yuet, T. (2013). Dietary supplementation with purified mulberry (Morus australis Poir) anthocyanins suppresses body weight gain in high-fat diet fed C57BL/6 mice. Food Chemistry, 141(1), 482–487. https://doi.org/10.1016/j.foodchem.2013.03.046

    Article  PubMed  CAS  Google Scholar 

  45. Tyl, C. E., & Bunzel, M. (2012). Antioxidant activity-guided fractionation of blue wheat (UC66049 Triticum aestivum L.). Journal of Agricultural Food Chemistry, 60(3), 731–739. https://doi.org/10.1021/jf203648x

    Article  PubMed  CAS  Google Scholar 

  46. Zhang, J., Hou, X., Ahmad, H., Zhang, H., Zhang, L., & Wang, T. (2014). Assessment of free radicals scavenging activity of seven natural pigments and protective effects in AAPH-challenged chicken erythrocytes. Food Chemistry, 145, 57–65. https://doi.org/10.1016/j.foodchem.2013.08.025

    Article  PubMed  CAS  Google Scholar 

  47. Hatami, M., Mortazavi, M., Baseri, Z., Khani, B., Rahimi, M., & Babaei, S. (2023). Antioxidant compounds in the treatment of Alzheimer’s disease: Natural, hybrid, and synthetic products. Evidence based Complementary and Alternative Medicine, 8056462, 12. https://doi.org/10.1155/2023/8056462

    Article  Google Scholar 

  48. Sharma, S., Sharma, Y. P., Bhardwaj, C., & Mehta, A. (2018). Quantification of amaroswerin and amarogentin in different parts of Swertia chirayita by chromatographic analysis. International Research Journal of Pure Applied Chemistry, 17(4), 1–7. https://doi.org/10.9734/IRJPAC/2018/47081

    Article  Google Scholar 

  49. Niiho, Y., Yamazaki, T., Nakajima, Y., Yamamota, T., Ando, H., & Hirai, Y. (2006). Gastroprotective effects of bitter principles isolated from Gentian root and Swertia herb on experimentally-induced gastric lesions in rats. Journal of Natural Medicines, 60, 82–88. https://doi.org/10.1007/s11418-005-0014-2

    Article  CAS  Google Scholar 

  50. Monteiro, A. F. M., Viana, J. O., Nayarisseri, A., Zondegoumba, E. N., Mendonça, J., Junior, F. J. B., Scotti, M. T., & Scotti, L. (2018). Computational studies applied to flavonoids against Alzheimer’s and Parkinson’s diseases. Oxidative Medicine and Cellular Longevity, 30, 7912765. https://doi.org/10.1155/2018/7912765El

    Article  Google Scholar 

  51. Kim, M. S., Young Lee, D., Sung, S. H., & Jeon, K. W. (2018). Anti-cholinesterase activities of hydrolysable tannins and polyhydroxytriterpenoid derivatives from Terminalia chebula Retz. Fruit Records of Natural Prodocts, 12(3), 284–289.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the King Saud University, Riyadh, Saudi Arabia, under Grant No. RSPD2023R696.

Author information

Authors and Affiliations

  1. Department of Chemistry, Government College of Engineering, Sengipatti, Thanjavur, 613402, Tamil Nadu, India

    Karunanithi Kalaimathi

  2. Division of Phytochemistry and Drug Design, Department of Biosciences, Rajagiri College of Social Sciences, Cochin, 683104, Kerala, India

    Srinivasan Prabhu & Singamoorthy Amalraj

  3. PG and Research Department of Botany, AVVM Sri Pushpam College (Autonomous) Poondi (Affiliated to Bharathidasan University), Thanjavur (Dist), 613503, Tamil Nadu, India

    Muniappan Ayyanar

  4. Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul, 05029, Korea

    Muthu Thiruvengadam

  5. Department of Botany and Microbiology, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia

    Kadaikunnan Shine

  6. PG & Research Department of Biotechnology, Microbiology and Bioinformatics, National College (Autonomous), Tiruchirappalli, 620001, Tamil Nadu, India

    Sitrarasu Vijaya Prabhu

Authors
  1. Karunanithi Kalaimathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Srinivasan Prabhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muniappan Ayyanar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muthu Thiruvengadam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kadaikunnan Shine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sitrarasu Vijaya Prabhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Singamoorthy Amalraj
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KK: investigation, formal analysis, molecular docking, and data maintenance. PS: conceptualization, methodology, writing draft, review and editing, and supervision, AM: investigation, formal analysis, critically reviewing and editing the article. TM: data conceptualization, data maintenance, and formal analysis. SK: conceptualization, methodology, fundraising, review and editing, and supervision. VPS: conceptualization, methodology, formal analysis, and review collection. AS: data collection and data interpretation.

Corresponding author

Correspondence to Srinivasan Prabhu.

Ethics declarations

Ethical Approval

This research does not require ethical approval.

Consent to Participate

Not applicable.

Consent for Publication

On behalf of the authors, I hereby assign the right of this entire article content to this journal.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 683 KB)

Supplementary file2 (CSV 18 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kalaimathi, K., Prabhu, S., Ayyanar, M. et al. Unravelling the Untapped Pharmacological Potential of Plant Molecules as Inhibitors of BACE1: In Silico Explorations for Alzheimer’s Disease. Appl Biochem Biotechnol (2023). https://doi.org/10.1007/s12010-023-04803-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12010-023-04803-4

Keywords

Search

Navigation