In Silico Identification of Novel Apolipoprotein E4 Inhibitor for Alzheimer’s Disease Therapy

Author(s): Saddia Bano , Muhammad Asif Rasheed , Farrukh Jamil , Muhammad Ibrahim* , Sumaira Kanwal* .

Journal Name: Current Computer-Aided Drug Design

Volume 15 , Issue 1 , 2019

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Graphical Abstract:


Introduction: Apolipoprotein E4 (ApoE) is a major genetic factor for developing Alzheimer’s disease (AD). It plays a vital role in brain to maintain a constant supply of neuronal lipids for rapid and dynamic membrane synthesis. Aggregation of beta amyloid plaques (Aβ) and neurofibrillary tangles in brain are responsible for onset of AD. The current study is designed to predict a drug against over activity of apoE4. 22 natural compounds (marine, microorganism and plant derivative) were used in current study.

Methods: These compounds were used as inhibitors to target apoE4 protein activity. Moreover, six synthetic compounds were docked with target protein to compare and analyze the docking results with natural compounds. S-Allyl-L-Cysteine, Epicatechin Gallate and Fulvic acid showed highest binding affinity (-7.1, - 7 and -7 kcal /mol respectively). Analysis of the docked complex showed that Epicatechin Gallate bonded with Gln156 and Asp35. Furthermore, Fulvic Acid showed hydrogen bonding with Glu27. Among synthetic compound, Tideglusib had highest binding affinity with target protein but did not show hydrogen bonding with any amino acid residue. Moreover, a natural compound S-Allyl-LCysteine also showed highest binding affinity but did not show hydrogen bonding with any amino acid residue.

Results and Conclusion: Our study highlighted Epicatechin Gallate as a potential lead compound on the basis of binding affinity and hydrogen bonding to inhibit the progression of AD.

Keywords: ApoE4, Alzheimer's disease, docking, bioinformatics, Cysteine, Epicatechin Gallate.

Wimo, A.; Jönsson, L.; Bond, J.; Prince, M.; Winblad, B. The worldwide economic impact of dementia 2010. Alzheimers Dement., (N Y), 2013, 9(1), 1-11. e3.,
(a) Huang, H.-J.; Chen, H.-Y.; Lee, C.-C.; Chen, C.Y.-C. Computational design of apolipoprotein E4 inhibitors for Alzheimer’s disease therapy from traditional Chinese medicine.BioMed Res. Int, 2014 2014.
(b) Gómez‐Isla, T.; Hollister, R.; West, H.; Mui, S.; Growdon, J.H.; Petersen, R.C.; Parisi, J.E.; Hyman, B.T. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol., 1997, 41(1), 17-24.
Corder, E.H.; Saunders, A.M.; Strittmatter, W.J.; Schmechel, D.E.; Gaskell, P.C.; Small, G.; Roses, A.D.; Haines, J.; Pericak-Vance, M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 1993, 261(5123), 921-923.
Pericak-Vance, M.; Bebout, J.; Gaskell, P.; Yamaoka, L.; Hung, W-Y.; Alberts, M.; Walker, A.; Bartlett, R.; Haynes, C.; Welsh, K. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. Journa. Hum. Genet., 1991, 48(6), 1034.
(a) Johnson, L.A.; Olsen, R.H.; Merkens, L.S.; DeBarber, A.; Steiner, R.D.; Sullivan, P.M.; Maeda, N.; Raber, J. Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner. Neurobiol. Dis., 2014, 64, 150-162.
(b) Raber, J.; Huang, Y.; Ashford, J.W. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol. Aging, 2004, 25(5), 641-650.
Strittmatter, W.J.; Saunders, A.M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G.S.; Roses, A.D.; Apolipoprotein, E. High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. , 1993, 90(5), 1977-1981.
Roses, A.D. Apolipoprotein E and Alzheimer’s disease: The tip of the susceptibility iceberg. Ann. N. Y. Acad. Sci., 1998, 855(1), 738-743.
van der Flier, W.M.; Pijnenburg, Y.A.; Fox, N.C.; Scheltens, P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE ɛ4 allele. Lancet The Neurol., 2011, 10(3), 280-288.
Dong, L-M.; Wilson, C.; Wardell, M.R.; Simmons, T.; Mahley, R.W.; Weisgraber, K.H.; Agard, D.A. Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J. Biol. Chem., 1994, 269(35), 22358-22365.
Tanzi, R.E.; Bertram, L. Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective. Cell, 2005, 120(4), 545-555.
(a) Risner, M.; Saunders, A.; Altman, J.; Ormandy, G.; Craft, S.; Foley, I.; Zvartau-Hind, M.; Hosford, D.; Roses, A. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. The Pharmaco J., 2006, 6(4), 246.
(b) Roses, A.D.; Saunders, A.M. Perspective on a pathogenesis and treatment of Alzheimer’s disease. Alzheimers Dement., 2006, 2(2), 59-70.
Kalita, P.; Sarma, R.; Parida, P.; Kiranmai, C.; Barthakur, M.; Reddy, P.V.B. in silico modelling and structural characterization of γ-aminobutyrate aminotransferase (GABA-AT). Indo Am. J. Pharma. Res., 2014, 4(10), 5066-5073.
Stahl, M.; Guba, W.; Kansy, M. Integrating molecular design resources within modern drug discovery research: The Roche experience. Drug Discov. Today, 2006, 11(7-8), 326-333.
(a) Conway, E.L. A review of the randomized controlled trials of tacrine in the treatment of Alzheimer’s disease: Methodologic considerations. Clin. Neuropharmacol., 1998, 21(1), 8-17.
(b) Goyal, M.; Grover, S.; Dhanjal, J.K.; Goyal, S.; Tyagi, C.; Chacko, S.; Grover, A. Novel natural structure corrector of ApoE4 for checking Alzheimer’s disease: Benefits from high throughput screening and molecular dynamics simulations. BioMed Res. Int., 2013, 2013
Mayeux, R.; Sano, M., Treatment of Alzheimer's disease. New Eng. J. Med., 1999, 341(22), 1670-1679; (b) Weisgraber, K.H. Apolipoprotein E: Structure-function relationships. In Advances in protein chemistry, Elsevier: 1994; Vol. 45, pp 249-302; (c) Calcul, L.; Zhang, B.; Jinwal, U.K.; Dickey, C.A.; Baker, B.J. Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease. Fut. Med. Chem., 2012, 4(13), 1751-1761
Burley, S.K.; Berman, H.M.; Christie, C.; Duarte, J.M.; Feng, Z.; Westbrook, J.; Young, J.; Zardecki, C. RCSB Protein Data Bank: Sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education. Protein Sci., 2018, 27(1), 316-330.
Lovell, S.C.; Davis, I.W.; Arendall, W.B.; De Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Cα geometry: ϕ, ψ and Cβ deviation. Proteins Structure, Function, and Bioinformatics, , 2003, 50(3), 437-450.
Li, C.; Gotz, J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nature reviews. Drug Discov., 2017, 16(12), 863-883.
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A. PubChem substance and compound databases. Nucleic Acids Res., 2015, 44(D1), D1202-D1213.
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. ACS Publications:2012
Gopalakrishnan, K.; Sowmiya, G.; Sheik, S.; Sekar, K. Ramachandran plot on the web (2.0). Protein Pept. Lett., 2007, 14(7), 669-671.
Desiraju, G.R.; Steiner, T. The weak hydrogen bond: in structural chemistry and biology; International Union of Crystal, 2001, Vol. 9, .
Panigrahi, S.K.; Desiraju, G.R. Strong and weak hydrogen bonds in the protein–ligand interface. Proteins Structure, Function, and Bioinformatics, , 2007, 67(1), 128-141.
Ahmed, R.; VanSchouwen, B.; Jafari, N.; Ni, X.; Ortega, J.; Melacini, G. Molecular Mechanism for the (−)-Epigallocatechin Gallate-Induced Toxic to Nontoxic Remodeling of Aβ Oligomers. J. Am. Chem. Soc., 2017, 139(39), 13720-13734.
Jia, J-J.; Zeng, X-S.; Song, X-Q.; Zhang, P-P.; Chen, L. Diabetes Mellitus and Alzheimer’s Disease: The Protection of Epigallocatechin-3-gallate in Streptozotocin Injection-Induced Models. Frontiers in Pharmacol., 2017, 8, 834.
Cascella, M.; Bimonte, S.; Muzio, M.R.; Schiavone, V.; Cuomo, A. The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: An overview of pre-clinical studies and translational perspectives in clinical practice. Infect. Agent. Cancer, 2017, 12, 36.
Mandel, S.A.; Amit, T.; Kalfon, L.; Reznichenko, L.; Weinreb, O.; Youdim, M.B. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J. Alzheimer’s Dis. JAD, 2008, 15(2), 211-222.
(a) Biasibetti, R.; Tramontina, A.C.; Costa, A.P.; Dutra, M.F.; Quincozes-Santos, A.; Nardin, P.; Bernardi, C.L.; Wartchow, K.M.; Lunardi, P.S.; Goncalves, C.A. Green tea (-)epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia. Behav. Brain Res., 2013, 236(1), 186-193.
(b) Rezai-Zadeh, K.; Arendash, G.W.; Hou, H.; Fernandez, F.; Jensen, M.; Runfeldt, M.; Shytle, R.D.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res., 2008, 1214, 177-187.
(c) Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.; Jeanniton, D.; Ehrhart, J.; Townsend, K.; Zeng, J.; Morgan, D.; Hardy, J.; Town, T.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci., 2005, 25(38), 8807-8814.
Shen, J.; Cheng, F.; Xu, Y.; Li, W.; Tang, Y. Estimation of ADME properties with substructure pattern recognition. J. Chem. Inf. Model., 2010, 50(6), 1034-1041.
Szklarczyk, D.; Franceschini, A.; Kuhn, M.; Simonovic, M.; Roth, A.; Minguez, P.; Doerks, T.; Stark, M.; Muller, J.; Bork, P. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res.,2010, 39(suppl_1), D561-D568.

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Article Details

Year: 2019
Page: [97 - 103]
Pages: 7
DOI: 10.2174/1573409914666181008164209
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