The Scientific World Journal

The Scientific World Journal / 2012 / Article
!A Letter to Editor for this article has been published. To view the article details, please click the ‘Letter to the Editor’ tab above.

Research Article | Open Access

Volume 2012 |Article ID 823201 | 4 pages | https://doi.org/10.1100/2012/823201

Molecular Basis of Inhibitory Activities of Berberine against Pathogenic Enzymes in Alzheimer's Disease

Academic Editor: Robert Perneczky
Received27 Oct 2011
Accepted16 Nov 2011
Published04 Jan 2012

Abstract

The natural isoquinoline alkaloid berberine possesses potential to treat Alzheimer's disease (AD) by targeting multiple pathogenic factors. In the present study, docking simulations were performed to gain deeper insights into the molecular basis of berberine's inhibitory effects against the important pathogenic enzymes of AD, that is, acetylcholinesterase, butyrylcholinesterase, and two isoforms of monoamine oxidase. It was found that the theoretical binding affinities of berberine to the four enzymes are very close to the experimental values, which verify the methodology. Further inspection to the binding modes found that hydrophobic interactions between the hydrophobic surface of berberine and neighboring hydrophobic residues are the principal forces contributing to the ligand-receptor interactions. Although berberine cation also has potential to form electrostatic interaction with neighboring residues, it is interesting to find that electrostatic force is excluded in the four cases unexpectedly. These results have important implications for the berberine-based anti-AD drug design.

1. Introduction

As a natural isoquinoline alkaloid isolated from the Chinese herb Rhizoma coptidis, berberine (Figure 1) has gained considerable attention because of its wide spectrum of biochemical and pharmacological potentials, including antioxidant, antiinflammatory, anticancer activities, and so forth, [16]. Alzheimer’s disease (AD) is the most common form of degenerative dementia with an estimated prevalence of 30 million people worldwide, and with the accelerated aging of human society, its prevalence is expected to rise steadily [710]. In recent years, multiple lines of evidence support that berberine also possesses potential to act as a multipotent agent to treat AD [1114]. For instance, many experimental studies reported that berberine exhibits inhibitory effects against several key enzymes implicated in the pathogenesis of AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO) [1422]. With the aim to elucidate the molecular basis of berberine’s inhibitory effects against the pathogenic enzymes in AD, in the present study, the binding modes of berberine with four enzymes, that is, AChE, BChE, MAO-A, and MAO-B, were investigated by means of docking simulations. The results indicate that hydrophobic interactions are the principal forces contributing to the binding of berberine to the four enzymes. Despite the cation ion in berberine structure (Figure 1) can interact readily with the negatively charged acidic residues, no electrostatic force is observed unexpectedly in the four cases. The findings have important implications for the berberine-based anti-AD drug design.

2. Methods

2.1. Structural Models

Structure coordinates for AChE, BChE, MAO-A, and MAO-B were taken from the Protein Data Bank (PDB codes: 1EA5 [23], 1P0I [24], 1O5 W [25], and 1GOS [26], resp.). The 3D structure of berberine was firstly constructed using standard geometric parameters of SYBYL software and then was optimized using Powell method with the Tripos force field (distance-dependent dielectric) to reach a final energy convergence gradient value of 0.001 kcal/mol.

2.2. Docking Methods

The Surflex-Dock program interfaced with SYBYL software is employed to perform docking experiments in this study, which uses an empirically derived scoring function based on the binding affinities of protein-ligand complexes and on their X-ray structures [27]. As a flexible docking method, Surflex-Dock has been proven to be efficient in treating numerous protein receptors [27, 28]. The active sites for four targets were selected on the basis of experimentally reported key residues, which play key roles in their catalytic activities [2326]. During the simulations, the Kollman-all atom charges were assigned to protein atoms using SYBYL software. For berberine molecule, 30 conformations were selected to dock with target in each run. Standard parameters were used to estimate the binding affinity characterized by Surflex-Dock scores. Surflex-Dock scores (total scores) are expressed in −log10() units to represent binding affinities [29, 30].

3. Results and Discussion

The theoretical binding constants of berberine to AChE, BChE, MAO-A, and MAO-B are estimated and listed in Table 1. It can be seen that berberine possesses inhibitory activity against the four enzymes and the respective binding affinities vary largely. The theoretical of berberine to AChE (0.66 μM), BChE (3.31 μM), MAO-A (105.2 μM), and MAO-B (66.0 μM) are very close to the experimental values (Table 1), which verify the accuracy of the present methodology. According to the theoretical , the inhibitory activity of berberine against AChE is the highest among the four enzymes, which is in agreement with the experimental results.


TargetsTheoretical 𝐾 𝑑 (μM)Experimental IC50 (μM)

AChE0.660.44 [14], 0.58 [15], 0.37 [16]
BChE3.313.44 [14]
MAO-A105.2126 [19]
MAO-B66.098.2 [20], 98.4 [21]

To elucidate the forces contributing to the binding affinity, the binding modes of berberine in AChE, BChE, MAO-A, and MAO-B are shown in Figure 2. From the molecular structure point of view, berberine has a large hydrophobic surface and a cation ion, which is ideal for interacting with the hydrophobic residues and the negatively charged acidic residues (Figure 1). As shown in Figure 2, the neighboring residues to berberine in the four enzymes are almost all aromatic and/or hydrophobic amino acids. Therefore, these residues can readily form hydrophobic interactions with the hydrophobic surface of berberine. According to Figure 2, there are eight hydrophobic residues (four phenylalanine, three tyrosine, and one tryptophan) interacting with berberine in AChE, while only six hydrophobic residues (one phenylalanine, two tyrosine, two tryptophan, and one isoleucine) with respect to the binding pocket in BChE. Also, a hydrogen bond is formed between berberine and Tyr121 in AChE (Figure 2), which will strengthen the binding affinity and enhance the inhibitory activity of berberine against AChE. These two aspects may account for the relatively stronger binding of berberine to AChE than BChE. In addition, there are less hydrophobic residues involved in the binding of berberine to MAO-A and MAO-B (Figure 2), which results in their much lower binding affinity.

Although berberine cation also has the potential to form electrostatic interaction with neighboring residues in four enzymes, it is interesting to find that as no corresponding negatively charged acidic residues exist at proper positions, no electrostatic interaction is observed. Therefore, according to the present results, the inhibitory activities of berberine against four targets mainly arise from hydrophobic interactions.

4. Conclusions

In conclusion, the theoretically estimated binding affinities of berberine to the four enzymes, AChE, BChE, MAO-A, and MAO-B, are very close to the experimental values. According to the binding modes, the hydrophobic interactions between berberine and surrounding hydrophobic residues in the enzymes play predominant roles, while electrostatic force is excluded in the binding of berberine to the four targets. These findings shed lights on the molecular basis of the inhibitory effects of berberine against the enzymes implicated in the pathogenesis of AD and will be helpful for the berberine-based anti-AD drug design.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (Grant no. 30800184).

References

  1. M. Imanshahidi and H. Hosseinzadeh, “Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine,” Phytotherapy Research, vol. 22, no. 8, pp. 999–1012, 2008. View at: Publisher Site | Google Scholar
  2. P. R. Vuddanda, S. Chakraborty, and S. Singh, “Berberine: a potential phytochemical with multispectrum therapeutic activities,” Expert Opinion on Investigational Drugs, vol. 19, no. 10, pp. 1297–1307, 2010. View at: Publisher Site | Google Scholar
  3. C. L. Kuo, C. W. Chi, and T. Y. Liu, “The anti-inflammatory potential of berberine in vitro and in vivo,” Cancer Letters, vol. 203, no. 2, pp. 127–137, 2004. View at: Publisher Site | Google Scholar
  4. Y. Sun, K. Xun, Y. Wang, and X. Chen, “A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs,” Anti-Cancer Drugs, vol. 20, no. 9, pp. 757–769, 2009. View at: Publisher Site | Google Scholar
  5. L. Račková, M. Májeková, D. Košt'álová, and M. Štefek, “Antiradical and antioxidant activities of alkaloids isolated from Mahonia aquifolium. Structural aspects,” Bioorganic & Medicinal Chemistry, vol. 12, no. 17, pp. 4709–4715, 2004. View at: Publisher Site | Google Scholar
  6. F. R. Stermitz, P. Lorenz, J. N. Tawara, L. A. Zenewicz, and K. Lewis, “Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5-methoxyhydnocarpin, a multidrug pump inhibitor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1433–1437, 2000. View at: Google Scholar
  7. C. Ballard, S. Gauthier, A. Corbett, C. Brayne, D. Aarsland, and E. Jones, “Alzheimer's disease,” The Lancet, vol. 377, no. 9770, pp. 1019–1031, 2011. View at: Publisher Site | Google Scholar
  8. D. M. Holtzman, J. C. Morris, and A. M. Goate, “Alzheimer's disease: the challenge of the second century,” Science Translational Medicine, vol. 3, no. 77, p. 77sr1, 2011. View at: Publisher Site | Google Scholar
  9. J. L. Cummings, “Alzheimer's disease,” The New England Journal of Medicine, vol. 351, no. 1, pp. 56–57, 2004. View at: Publisher Site | Google Scholar
  10. B. L. Plassman, K. M. Langa, G. G. Fisher et al., “Prevalence of dementia in the United States: the aging, demographics, and memory study,” Neuroepidemiology, vol. 29, no. 1-2, pp. 125–132, 2007. View at: Publisher Site | Google Scholar
  11. F. Zhu and C. Qian, “Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1 beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease,” BMC Neuroscience, vol. 7, article 78, 2006. View at: Publisher Site | Google Scholar
  12. H-F. Ji and L. Shen, “Berberine: a potential multipotent natural product to combat Alzheimer's disease,” Molecules, vol. 16, no. 8, pp. 6732–6740, 2011. View at: Publisher Site | Google Scholar
  13. M. Ye, S. Fu, R. Pi, and F. He, “Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research,” Journal of Pharmacy and Pharmacology, vol. 61, no. 7, pp. 831–837, 2009. View at: Publisher Site | Google Scholar
  14. H. A. Jung, B. S. Min, T. Yokozawa, J. H. Lee, Y. S. Kim, and J. S. Choi, “Anti-Alzheimer and antioxidant activities of coptidis rhizoma alkaloids,” Biological & Pharmaceutical Bulletin, vol. 32, no. 8, pp. 1433–1438, 2009. View at: Publisher Site | Google Scholar
  15. K. Ingkaninan, P. Phengpa, S. Yuenyongsawad, and N. Khorana, “Acetylcholinesterase inhibitors from Stephania venosa tuber,” Journal of Pharmacy and Pharmacology, vol. 58, no. 5, pp. 695–700, 2006. View at: Publisher Site | Google Scholar
  16. L. Huang, Z. Luo, F. He, A. Shi, F. Qin, and X. Li, “Berberine derivatives, with substituted amino groups linked at the 9-position, as inhibitors of acetylcholinesterase/butyrylcholinesterase,” Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 22, pp. 6649–6652, 2010. View at: Publisher Site | Google Scholar
  17. L. Huang, A. Shi, F. He, and X. Li, “Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors,” Bioorganic & Medicinal Chemistry, vol. 18, no. 3, pp. 1244–1251, 2010. View at: Publisher Site | Google Scholar
  18. D. K. Kim, K. T. Lee, N. I. Baek et al., “Acetylcholinesterase inhibitors from the aerial parts of Corydalis speciosa,” Archives of Pharmacal Research, vol. 27, no. 11, pp. 1127–1131, 2004. View at: Google Scholar
  19. L. D. Kong, C. H. K. Cheng, and R. X. Tan, “Monoamine oxidase inhibitors from rhizoma of Coptis chinensis,” Planta Medica, vol. 67, no. 1, pp. 74–76, 2001. View at: Publisher Site | Google Scholar
  20. S. S. Lee, M. Kai, and M. K Lee, “Effects of natural isoquinoline alkaloids on monoamine oxidase activity in mouse brain: inhibition by berberine and palmatine,” Medical Science Research, vol. 27, no. 11, pp. 749–751, 1999. View at: Google Scholar
  21. J. Castillo, J. Hung, M. Rodriguez, E. Bastidas, I. Laboren, and A. Jaimes, “LED fluorescence spectroscopy for direct determination of monoamine oxidase B inactivation,” Analytical Biochemistry, vol. 343, no. 2, pp. 293–298, 2005. View at: Publisher Site | Google Scholar
  22. S. K. Kulkarni and A. Dhir, “On the mechanism of antidepressant-like action of berberine chloride,” European Journal of Pharmacology, vol. 589, no. 1–3, pp. 163–172, 2008. View at: Publisher Site | Google Scholar
  23. H. Dvir, H. L. Jiang, D. M. Wong et al., “X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement,” Biochemistry, vol. 41, no. 35, pp. 10810–10818, 2002. View at: Publisher Site | Google Scholar
  24. Y. Nicolet, O. Lockridge, P. Masson, J. C. Fontecilla-Camps, and F. Nachon, “Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products,” The Journal of Biological Chemistry, vol. 278, no. 42, pp. 41141–41147, 2003. View at: Publisher Site | Google Scholar
  25. J. Ma, M. Yoshimura, E. Yamashita, A. Nakagawa, A. Ito, and T. Tsukihara, “Structure of rat monoamine oxidase A and its specific recognitions for substrates and inhibitors,” Journal of Molecular Biology, vol. 338, no. 1, pp. 103–114, 2004. View at: Publisher Site | Google Scholar
  26. C. Binda, P. Newton-Vinson, F. Hubálek, D. E. Edmondson, and A. Mattevi, “Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders,” Nature Structural Biology, vol. 9, no. 1, pp. 22–26, 2001. View at: Publisher Site | Google Scholar
  27. A. N. Jain, “Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine,” Journal of Medicinal Chemistry, vol. 46, no. 4, pp. 499–511, 2003. View at: Publisher Site | Google Scholar
  28. E. Kellenberger, J. Rodrigo, P. Muller, and D. Rognan, “Comparative evaluation of eight docking tools for docking and virtual screening accuracy,” Proteins, vol. 57, no. 2, pp. 225–242, 2004. View at: Publisher Site | Google Scholar
  29. P. A. Holt, J. B. Chaires, and J. O. Trent, “Molecular docking of intercalators and groove-binders to nucleic adds using autodock and surflex,” Journal of Chemical Information and Modeling, vol. 48, no. 8, pp. 1602–1615, 2008. View at: Publisher Site | Google Scholar
  30. M. Yang, L. Zhou, Z. Zuo, X. Tang, J. Liu, and X. Ma, “Structure-based virtual screening for glycosyltransferase51,” Molecular Simulation, vol. 34, no. 9, pp. 849–856, 2008. View at: Publisher Site | Google Scholar

Copyright © 2012 Hong-Fang Ji and Liang Shen. 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.


More related articles

2126 Views | 1466 Downloads | 19 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.