Phytochemical compounds against mild cognitive impairment key proteins: An in-silico approach

Cristian Gonzalez-Ruiz; Isabel Hidalgo; Andrés Portilla-Martínez; Iván Rubio-Gayosso; Hermelinda Salgado-Ceballos; Omar Fabela-Sánchez; Jorge Bernal-Hernández; Miguel Ortiz-Flores

doi:10.7324/JAPS.2025.209505

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Abstract

Mild cognitive impairment (MCI) is defined as an intermediate stage between normal age-related cognitive decline and pathological cognitive deterioration associated with aging, which course with alterations in one or more cognitive domains and could progress to a major neurocognitive disorder; we investigate five critical proteins involved in the pathophysiological process of MCI: Glycogen synthase 3-β (GSK3β), β-secretase (BACE1), Glutamate transporter associated protein 3–18 (GTRAP3-18), Pregnane X receptor (PXR), and epidermal growth factor receptor (EGFR). We evaluated 2,568 phytochemical compounds as potential ligands of the best conformations of proteins, minimized with 100 ns of molecular dynamics (MDs), which have biological effects on central nervous system disease. All compounds were subjected to virtual screening to obtain the best ligand based on the docking score, then, 1,000 independent docking assays were performed to corroborate the binding site; Root Mean Square Deviation, frequency, and interacting atoms were calculated. Finally, the MD of the best ligand-protein complex was developed. The top probable ligand for each protein was dioscin for BACE1, quadrigeminal-A for GSK3β and GTRAP3-18, psychotridine for PXR and EGFR. This research emphasizes various phytochemicals that influence dysregulated proteins in MCI, offering details on their binding affinities and molecular interactions at the active sites of each receptor.

Keyword: Mild cognitive impairment phytochemical compounds virtual screening molecular dynamics β-secretase GSK3β

Citation:

Gonzalez-Ruiz C, Hidalgo I, Portilla-Martínez A, Rubio- Gayosso I, Salgado-Ceballos H, Fabela-Sánchez O, Bernal- Hernández J, Ortiz-Flores M. Phytochemical compounds against mild cognitive impairment key proteins: An in-silico approach. J Appl Pharm Sci. 2025. Online First. http://doi.org/10.7324/JAPS.2025.221899

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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1. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment. Arch Neurol. 1999 Mar 1;56(3):303. https://doi.org/10.1001/archneur.56.3.303

2. Jongsiriyanyong S, Limpawattana P. Mild cognitive impairment in clinical practice: a review article. A J Alzheimer's Dis Other Dementiasr. 2018 Dec 1;33(8):500-7. https://doi.org/10.1177/1533317518791401

3. Mufson EJ, Binder L, Counts SE, DeKosky ST, deToledo-Morrell L, Ginsberg SD, et al. Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 2012 Jan 19;123(1):13-30. https://doi.org/10.1007/s00401-011-0884-1

4. Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, et al. Increased plasma beta-secretase 1 may predict conversion to Alzheimer's disease dementia in individuals with mild cognitive impairment. Biol Psychiatry. 2018 Mar;83(5):447-55. https://doi.org/10.1016/j.biopsych.2017.02.007

5. Forlenza O V., Torres CA, Talib LL, de Paula VJ, Joaquim HPG, Diniz BS, et al. Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer's disease. J Psychiatr Res. 2011 Feb;45(2):220-4. https://doi.org/10.1016/j.jpsychires.2010.06.002

6. Kasper S, Bancher C, Eckert A, Förstl H, Frölich L, Hort J, et al. Management of mild cognitive impairment (MCI): the need for national and international guidelines. World J Biol Psychiatry. 2020 Sep 13;21(8):579-94. https://doi.org/10.1080/15622975.2019.1696473

7. Zhang J, Wang Y, Dong X, Liu J. Crocetin attenuates inflammation and amyloid-β accumulation in APPsw transgenic mice. Immunity Ageing. 2018 Dec 30;15(1):24. https://doi.org/10.1186/s12979-018-0132-9

8. Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment. Hypertension. 2012 Sep;60(3):794-801. https://doi.org/10.1161/HYPERTENSIONAHA.112.193060

9. Boespflug EL, Eliassen JC, Dudley JA, Shidler MD, Kalt W, Summer SS, et al. Enhanced neural activation with blueberry supplementation in mild cognitive impairment. Nutr Neurosci. 2018 Apr 21;21(4):297-305. https://doi.org/10.1080/1028415X.2017.1287833

10. Kumar Gp, Khanum F. Neuroprotective potential of phytochemicals. Pharmacogn Rev. 2012;6(12):81. https://doi.org/10.4103/0973-7847.99898

11. Yan R, Vassar R. Targeting the β secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 2014 Mar;13(3):319-29. https://doi.org/10.1016/S1474-4422(13)70276-X

12. Hampel H, Vassar R, De Strooper B, Hardy J, Willem M, Singh N, et al. The β-Secretase BACE1 in Alzheimer's Disease. Biol Psychiatry. 2021 Apr;89(8):745-56. https://doi.org/10.1016/j.biopsych.2020.02.001

13. Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N. Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production. Mol Cell Biol. 2008 Jun 1;28(11):3663-71. https://doi.org/10.1128/MCB.02185-07

14. Chen G fang, Xu T hai, Yan Y, Zhou Y ren, Jiang Y, Melcher K, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017 Sep 17;38(9):1205-35. https://doi.org/10.1038/aps.2017.28

15. Zhang X, Song W. The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimers Res Ther. 2013;5(5):46. https://doi.org/10.1186/alzrt211

16. Muralidar S, Ambi SV, Sekaran S, Thirumalai D, Palaniappan B. Role of tau protein in Alzheimer's disease: the prime pathological player. Int J Biol Macromol. 2020 Nov;163:1599-617. https://doi.org/10.1016/j.ijbiomac.2020.07.327

17. Aoyama K, Nakaki T. Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis. Int J Mol Sci. 2012 Sep 20;13(12):12017-35. https://doi.org/10.3390/ijms130912017

18. Watabe M, Aoyama K, Nakaki T. A dominant role of GTRAP3-18 in neuronal glutathione synthesis. J Neurosci. 2008 Sep 17;28(38): 9404-13. https://doi.org/10.1523/JNEUROSCI.3351-08.2008

19. Chai AB, Leung GKF, Callaghan R, Gelissen IC. P-glycoprotein: a role in the export of amyloid-β in Alzheimer's disease? FEBS J. 2020 Feb 9;287(4):612-25. https://doi.org/10.1111/febs.15148

20. Ott M, Fricker G, Bauer B. Pregnane X Receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR. J Pharmacol Exp Therap. 2009 Apr;329(1):141-9. https://doi.org/10.1124/jpet.108.149690

21. Hussain B, Fang C, Chang J. Blood-brain barrier breakdown: an emerging biomarker of cognitive impairment in normal aging and dementia. Front Neurosci. 2021 Aug 19;15:688090. https://doi.org/10.3389/fnins.2021.688090

22. Tavassoly O, Sato T, Tavassoly I. Inhibition of brain epidermal growth factor receptor activation: a novel target in neurodegenerative diseases and brain injuries. Mol Pharmacol. 2020 Jul;98(1):13-22. https://doi.org/10.1124/mol.120.119909

23. Romano R, Bucci C. Role of EGFR in the nervous system. Cells. 2020 Aug 12;9(8):1887. https://doi.org/10.3390/cells9081887

24. Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021 Jan 8;49(D1):D1388-95. https://doi.org/10.1093/nar/gkaa971

25. Neveu V, Perez-Jimenez J, Vos F, Crespy V, du Chaffaut L, Mennen L, et al. Phenol-explorer: an online comprehensive database on polyphenol contents in foods. Database. 2010 Jul 30;2010(0):bap024- bap024. https://doi.org/10.1093/database/bap024

26. Harun S, Abdullah-Zawawi MR, A-Rahman MRA, Muhammad NAN, Mohamed-Hussein ZA. SuCComBase: a manually curated repository of plant sulfur-containing compounds. Database. 2019 Jan 1;2019: baz021. https://doi.org/10.1093/database/baz021

27. Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, et al. ChEBI in 2016: improved services and an expanding collection of metabolites. Nucleic Acids Res. 2016 Jan 4;44(D1):D1214-9. https://doi.org/10.1093/nar/gkv1031

28. Blaževi? I, Montaut S, Bur?ul F, Olsen CE, Burow M, Rollin P, et al. Glucosinolate structural diversity, identification, chemical synthesis and metabolism in plants. Phytochemistry. 2020 Jan;169:112100. https://doi.org/10.1016/j.phytochem.2019.112100

29. Sterling T, Irwin JJ. ZINC 15 - Ligand discovery for everyone. J Chem Inf Model. 2015 Nov 23;55(11):2324-37. https://doi.org/10.1021/acs.jcim.5b00559

30. O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: an open chemical toolbox. J Cheminform. 2011 Dec 7;3(1):33. https://doi.org/10.1186/1758-2946-3-33

31. Burley SK, Bhikadiya C, Bi C, Bittrich S, Chen L, Crichlow G V, et al. RCSB protein data bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Res. 2021 Jan 8;49(D1):D437-51. https://doi.org/10.1093/nar/gkaa1038

32. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021 Aug 26;596(7873):583-9. https://doi.org/10.1038/s41586-021-03819-2

33. Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 2022 Jan 7;50(D1):D439-44. https://doi.org/10.1093/nar/gkab1061

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