MOLECULAR DOCKING OF LION’S MANE BIOACTIVE COMPOUNDS AS BETA-SECRETASE INHIBITORS FOR ALZHEIMER’S DISEASE

NOURA BERAKDAR; SUNDUS J YASEEN; AZHAR MALEK; MOHMAD EIAD ALRAAI

doi:10.22159/ijls.2025v13.56432

Authors

NOURA BERAKDAR Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, University of Kalamoon, Deir Atiyah, Syrian Arab Republic
SUNDUS J YASEEN Department of Biochemistry and Microbiology, Faculty of Pharmacy, University of Kalamoon, Deir Atiyah, Syrian Arab Republic
AZHAR MALEK Department of Phytochemistry and Natural Products, Faculty of Pharmacy, University of Kalamoon, Deir Atiyah, Syrian Arab Republic
MOHMAD EIAD ALRAAI Department of Biochemistry and Microbiology, Faculty of Pharmacy, University of Kalamoon, Deir Atiyah, Syrian Arab Republic

DOI:

https://doi.org/10.22159/ijls.2025v13.56432

Keywords:

Lion’s mane, Alzheimer’s disease, Beta-secretase, Hericenone, Molegro virtual docker

Abstract

Objectives: Lion’s Mane is a medicinal mushroom that has attracted significant interest due to its proposed neuroprotective activity. This has led to research into its potential uses in neurological diseases such as Alzheimer’s. Alzheimer’s disease is a neurodegenerative disease characterized by a progressive decline in mental function. Pathologically, the disease is associated with the deposition of amyloid-beta plaques and neurofibrillary tangles within the brain. Beta-secretase is a key enzyme in the amyloid genesis pathway. Therefore, beta-secretase is considered a promising therapeutic target to halt the development and progression of Alzheimer’s disease.

Purpose: This research aims to explore the effect of the active compounds hericinone present in Lion’s Mane mushroom as a beta-secretase inhibitor by performing the docking process using Molegro Virtual Docker.

Methods: This study conducted a docking study of beta-secretase and some hericinones. Among them, the optimal binding energy of hericinones B was determined after meeting the drug-drug similarity criteria.

Results: The binding energy of the target beta-secretase to hericinone B was calculated to be −168 kcal/mol. This energy compares favorably with the binding energy of known ligand complexes to the target, which is −164 kcal/mol. The docking process involving the selected beta-secretase enzyme (Protein Data Bank ID-5QCU) was performed using Molegro. This process is consistent with the five Lipinski guidelines and demonstrates the drug’s likelihood and bioavailability.

Conclusion: Hericinone B was found to be the best compound that achieved better inhibition energy than the basic ligand. This is due to its chemical structural characteristics, its combination of lipophilic and polar regions, its hydrogen bonding ability, and the specific spatial arrangement of functional groups, which likely allows it to bind to a specific target.

References

1. Kocahan S, Doğan Z. Mechanisms of Alzheimer’s disease pathogenesis and prevention: The brain, neural pathology, N-methyl-D-aspartate receptors, tau protein and other risk factors. Clin Psychopharmacol Neurosci 2017;15:1-8.

2. Ju Y, Tam KY. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease. Neural Regen Res 2022;17:543.

3. Cole SL, Vassar R. The Alzheimer’s disease Beta-secretase enzyme, BACE1. Mol Neurodegener 2007;2:22.

4. Hampel H, Vassar R, De Strooper B, Hardy J, Willem M, Singh N, et al. The b-secretase BACE1 in Alzheimer’s disease. Biol Psychiatry 2020;89:745-56.

5. Banerjee S, Gupta S, Raj R, Gupta M. Unlocking the potential of Lion’s mane mushroom (Hericium erinaceus). J Appl Natural Sci 2024;16:39-50.

6. Cha S, Bell L, Shukitt-Hale B, Williams CM. A review of the effects of mushrooms on mood and neurocognitive health across the lifespan. Neurosci Biobehav Rev 2024;158:105548.

7. Contato AG, Conte-Junior CA. Lion’s mane mushroom (Hericium erinaceus): A neuroprotective fungus with antioxidant, anti-inflammatory, and antimicrobial potential-a narrative review. Nutrients 2025;17:1307.

8. Available from: https://www.rcsb.org/structure/5qcu

9. Kawagishi, H, Ando M, Shinba K, Sakamoto H, Yoshida S, Ojima F, et al. Chromans, hericenones F, G and H from the mushroom Hericium erinaceum. Phytochemistry 1992;32:175-8.

10. Ma BJ, Shen JW, Yu HY, Ruan Y, Wu TT, Zhao X. Hericenones and erinacines: Stimulators of nerve growth factor (NGF) biosynthesis inHericium erinaceus. Mycology 2010;1:92-8.

11. Lee LY, Li IC, Chen WP, Tsai YT, Chen CC, Tung KC. Thirteen-week oral toxicity evaluation of erinacine A enriched lion’s mane medicinal mushroom, Hericium erinaceus (Agaricomycetes), mycelia in sprague-dawley rats. Int J Med Mushrooms 2019;21:401-11.

12. Muhanna M, Lund I, Bromberg M, Wicks P, Benatar M, Barnes B, et al. ALSUntangled #73: Lion’s Mane. Amyotroph Lateral Scler Frontotemporal Degener 2023;25:420-3.

13. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-a#section=structures

14. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-b

15. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-c

16. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-d#section=computed-descriptors

17. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-e

18. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-g#section=3d-status

19. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-h

20. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-j

21. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/ hericenone-k

22. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/6900707 7#section=computed-properties

23. Bitencourt-Ferreira G, De Azevedo WF Jr. Molegro virtual docker for docking. Methods Mol Biol 2019;2053:149-67.

24. Thomas G. Medicinal Chemistry. 2nd ed. England: University of Portsmouth; 2015. p. 9-10.

25. Kerns EH, Di L. Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. Amsterdam: Academic Press is an Imprint of Elsevier; 2015. p. 6-120.

26. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3-26.

27. Lin G, Liu W, Zhang F, Linhardt RJ, Wang X. Bioactive substances in Hericium erinaceus and their biological properties: A review. Food Sci Hum Wellness 2024;13:1825-44.

28. Kobayashi S, Tamanoi H, Hasegawa Y, Segawa Y, Masuyama A. Divergent synthesis of bioactive resorcinols isolated from the fruiting bodies of Hericium erinaceum: Total syntheses of hericenones A, B, and I, hericenols B-D, and erinacerins A and B. J Org Chem 2014;79:5227-38.

29. Diling C, Tianqiao Y, Jian Y, Chaoqun Z, Ou S, Yizhen X. Docking studies and biological evaluation of a potential β-secretase inhibitor of 3-hydroxyhericenone F from Hericium erinaceus. Front Pharmacol 2017;8:219.

30. Hunt CE, Turner AJ. Cell biology, regulation and inhibition of beta-secretase (BACE-1). FEBS J 2009;276:1845-59.

31. De Oliveira AM, Rudrapal M. Introduction to drug design and discovery. In: Computer Aided Drug Design (CADD): From Ligand- Based Methods to Structure-Based Approaches. Netherlands: Elsevier; 2022. p. 1-15.

32. Wermuth CG, Ganellin CR, Lindberg P, Mitchard M. Textbook of Drug Design and Discovery. 5th ed. United States: CRC Press; 2016.