Inhibitory Mechanism of An Anticancer Drug, Bexarotene Against Amyloid β Peptide Aggregation: Repurposing Via Neuroinformatics Approach

Author(s): Nousheen Bibi*, Syed M.D. Rizvi, Abida Batool, Mohammad A. Kamal*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 27 , 2019

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Background: Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed.

Methods: In the present study, we have attempted to decipher the mechanistic aspects of the anti-aggregation potential of bexarotene by using the computational biology approach.

Results: We have observed the effect of ‘Aβ-bexarotene’ interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). A deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene.

Conclusion: Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ- peptide aggregation by applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entities against AD.

Keywords: Alzheimer disease, amyloid β-peptide (Aβ), bexarotene, beta secretase, molecular docking simulations, receptor for advanced glycation end products.

Cipriani G, Vedovello M, Nuti A, Di Fiorino M. Aggressive behavior in patients with dementia: correlates and management. Geriatr Gerontol Int 2011; 11(4): 408-13.
Batool A, Kamal MA, Rizvi S, Rashid S. Topical discoveries on multi-target approach to manage Alzheimer’s disease. Curr Drug Metab 2018; 19(8): 704-13.
Kar S, Slowikowski SP, Westaway D, Mount HT. Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 2004; 29(6): 427.
Ubhi K, Masliah E. Alzheimer’s disease: recent advances and future perspectives. J Alzheimers Dis 2013; 33(s1): S185-94.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
De Strooper B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 2010; 90(2): 465-94.
Endres K, Fahrenholz F. Regulation of alpha-secretase ADAM10 expression and activity. Exp Brain Res 2012; 217(3-4): 343-52.
Prox J, Rittger A, Saftig P. Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin. Exp Brain Res 2012; 217(3-4): 331-41.
Cohen SI, Linse S, Luheshi LM, et al. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci 2013; 110(24): 9758-63.
Balbach JJ, Petkova AT, Oyler NA, et al. Supramolecular structure in full-length Alzheimer’s β-amyloid fibrils: evidence for a parallel β-sheet organization from solid-state nuclear magnetic resonance. J Biophys 2002; 83(2): 1205-16.
Olofsson A, Sauer-Eriksson AE, Öhman A. The solvent protection of Alzheimer amyloid-β-(1–42) fibrils as determined by solution NMR spectroscopy. J Biochem 2006; 281(1): 477-83.
Lührs T, Ritter C, Adrian M, et al. 3D structure of Alzheimer's amyloid-β (1–42) fibrils. Proc Natl Acad Sci 2005; 102(48): 17342-7.
Török M, Milton S, Kayed R, et al. Structural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J Biochem 2002; 277(43): 40810-5.
Masuda Y, Uemura S, Nakanishi A, et al. Verification of the C-terminal intramolecular β-sheet in Aβ42 aggregates using solid-state NMR: implications for potent neurotoxicity through the formation of radicals. Bioorg Med Chem Lett 2008; 18(11): 3206-10.
Ahmed M, Davis J, Aucoin D, et al. Structural conversion of neurotoxic amyloid-β 1–42 oligomers to fibrils. Nat Struct Mol Biol 2010; 17(5): 561.
Habchi J, Arosio P, Perni M, et al. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease. Sci Adv 2016; 2(2)e1501244
Evans J. anticancer drug bexarotene inhibits build-up of toxic Alzheimer’s protein. Caring Ages 2016; 17(4): 11.
Landreth GE, Cramer PE, Lakner MM, et al. Response to comments on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 2013; 340(6135): 924-g.
Fitz NF, Cronican AA, Lefterov I, Koldamova R. Comments on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 2013; 340(6135): 924-c.
Price AR, Xu G, Siemienski ZB, et al. Response to comments on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 2013; 340(6135): 924-d.
Tesseur I, Lo AC, Roberfroid A, et al. Comments on “ApoEdirected therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 2013; 340(6135): 924-e.
Veeraraghavalu K, Zhang C, Miller S, et al. Comments on “ApoEdirected therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 2013; 340(6135): 924-f.
Tousi B. The emerging role of bexarotene in the treatment of Alzheimer’s disease: current evidence. Neuropsychiatr Dis Treatment 2015; 11: 311.
Cleveland Clinic. Bexarotene Amyloid Treatment for Alzheimer’s Disease (BEAT-AD). Available from:; show/NCT01782742 NLM identifier: NCT01782742. Accessed on: Sep 14,. 2014.
Norgan AP, Coffman PK, Kocher JP, Katzmann DJ, Sosa CP. Multilevel parallelization of AutoDock 4.2. J Cheminform 2011; 3(1): 12.
Duhovny D, Nussinov R, Wolfson HJ. Efficient unbound docking of rigid molecules. In International workshop on algorithms in bioinformatics 2002 Sep 17; Springer, Berlin, Heidelberg.. 185-200.
Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 2005; 33(suppl_2): W363-7.
Yang Z, Lasker K, Schneidman-Duhovny D, et al. UCSF Chimera, modeller, and IMP: an integrated modeling system. J Struct Biol 2012; 179(3): 269-78.
Gao YD, Huang JF. An extension strategy of Discovery Studio 2.0 for non-bonded interaction energy automatic calculation at the residue level. Dongwuxue Yanjiu 2011; 32(3): 262-6.
Baugh EH, Lyskov S, Weitzner BD, Gray JJ. Real-time PyMOL visualization for Rosetta and PyRosetta. PLoS One 2011; 6(8)e21931
Laskowski RA, Swindells MB. LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51(10): 2778-86.

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Article Details

Year: 2019
Page: [2989 - 2995]
Pages: 7
DOI: 10.2174/1381612825666190801123235
Price: $65

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