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Current Drug Discovery Technologies

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ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

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Research Article

In Silico Inhibition of BACE-1 by Selective Phytochemicals as Novel Potential Inhibitors: Molecular Docking and DFT Studies

Author(s): Nadia Arif, Andleeb Subhani, Waqar Hussain and Nouman Rasool*

Volume 17, Issue 3, 2020

Page: [397 - 411] Pages: 15

DOI: 10.2174/1570163816666190214161825

Price: $65

TIMBC 2025
Abstract

Background: Alzheimer’s Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings.

Objective: This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis.

Methods: A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals.

Results: The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1.

Conclusion: Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.

Keywords: ADMET, BACE-1, Molecular Docking, DFT, phytochemicals, in silico inhibition.

Graphical Abstract

[1]
Russo C, Schettini G, Saido TC, et al. Presenilin-1 mutations in Alzheimer’s disease. Nature 2000; 405(6786): 531-2.
[http://dx.doi.org/10.1038/35014735] [PMID: 10850703]
[2]
Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 2001; 414(6864): 643-8.
[http://dx.doi.org/10.1038/414643a] [PMID: 11740561]
[3]
Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9(12): 1520-5.
[http://dx.doi.org/10.1038/nn1797] [PMID: 17099708]
[4]
Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005; 25(50): 11693-709.
[http://dx.doi.org/10.1523/JNEUROSCI.2766-05.2005] [PMID: 16354928]
[5]
Dominguez D, Tournoy J, Hartmann D, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 2005; 280(35): 30797-806.
[http://dx.doi.org/10.1074/jbc.M505249200] [PMID: 15987683]
[6]
Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 2015; 18(6): 800-6.
[http://dx.doi.org/10.1038/nn.4018]
[7]
Gilman S. Oxford American Handbook of Neurology. Oxford, UK: OxfordUniversity Press 2010.
[8]
World Health Organization, WHO Mental Health Gap Action Programme (mhGAP). http://www.who.int/mental_health/mhgap/en/2008.
[9]
Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120(3): 885-90.
[http://dx.doi.org/10.1016/S0006-291X(84)80190-4] [PMID: 6375662]
[10]
Lee VM-Y, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 1991; 251(4994): 675-8.
[http://dx.doi.org/10.1126/science.1899488] [PMID: 1899488]
[11]
Haass C. Take five--BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid beta-peptide generation. EMBO J 2004; 23(3): 483-8.
[http://dx.doi.org/10.1038/sj.emboj.7600061] [PMID: 14749724]
[12]
Francis R, McGrath G, Zhang J, et al. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002; 3(1): 85-97.
[http://dx.doi.org/10.1016/S1534-5807(02)00189-2] [PMID: 12110170]
[13]
Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM. Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J Biol Chem 2000; 275(4): 2568-75.
[http://dx.doi.org/10.1074/jbc.275.4.2568] [PMID: 10644715]
[14]
Hasler CM. Blumberg JB. Symposium on Phytochemicals: Biochemistry and Physiology. Am Society Nutr Sci Nutr 1999. 129: 756S-757S..
[15]
Hasler CM, Blumberg JB. Phytochemicals: biochemistry and physiology. Introduction. J Nutr 1999; 129(3): 756S-7S.
[http://dx.doi.org/10.1093/jn/129.3.756S] [PMID: 10082785]
[16]
Wadood A, Ahmed N, Shah L, Ahmad A, Hassan H, Shams S. In silico drug design, An approach which revolutionises the drug discovery process. Drug Des Devel Ther 2013.
[17]
Kaczanowski S, Zielenkiewicz P. Why similar protein sequences Encode similar three M dimensional structures. Theor Chem Acc 2010; 125: 543-50.
[http://dx.doi.org/10.1007/s00214-009-0656-3]
[18]
17.Acquati F., Accarino M., Nucci C., Fumagalli P., Jovine L., Ottolenghi S, Taramelli. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett 2000; 468: 59-64.
[http://dx.doi.org/10.1016/S0014-5793(00)01192-3]
[19]
Cai H, Wang Y, McCarthy D, et al. BACE1 is the major β-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001; 4(3): 233-4.
[http://dx.doi.org/10.1038/85064] [PMID: 11224536]
[20]
Acquati F, Accarino M, Nucci C, et al. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett 2000; 468(1): 59-64.
[http://dx.doi.org/10.1016/S0014-5793(00)01192-3] [PMID: 10683441]
[21]
Johnson M, Zaretskaya I, Raytselis Y, Merezhuk Y, McGinnis S, Madden TL. NCBI BLAST: a better web interface Nucleic Acids Res 2008; 36(Web Server issue): W5-9
[PMID: 18440982]
[22]
Webb B, Sali A. Comparative protein structure modelling using Modeller. Curr Protoc Protein Sci 2014; 2-9.
[PMID: 27322406] [http://dx.doi.org/10.1002/cpbi.3]
[23]
Lee SK, Park SH, Lee IH, No KT. PreADMET Ver v20. Seoul, Korea: BMDRC 2007.
[24]
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(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[25]
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[26]
Morris GM, Huey R, Olson AJ. Using autoblock for ligand‐receptor docking. Curr Protoc Bioinformatics 2008; 24: 8.14.1-40..
[http://dx.doi.org/10.1002/0471250953.bi0814s24]
[27]
Gill PM, Johnson BG, Pople JA, Frisch MJ. The performance of the Becke-Lee-Yang-Parr (B-LYP) density functional theory with various basis sets. Chem Phys Lett 1992; 197(4–5): 499-505.
[http://dx.doi.org/10.1016/0009-2614(92)85807-M]
[28]
Neese F. The ORCA program system, Wiley Interdisciplinary Reviews. Rev Comput Mol Sci 2012; 2(1): 73-8.
[http://dx.doi.org/10.1002/wcms.81]
[29]
Gogoi D, Baruah VJ, Chaliha AK, Kakoti BB, Sarma D, Buragohain AK. Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening. Comput Biol Chem 2017; 69: 28-40.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.04.005] [PMID: 28552695]
[30]
Kavitha R, Karunagaran S, Chandrabose SS, Lee KW, Meganathan C. Pharmacophore modeling, virtual screening, molecular docking studies and density functional theory approaches to identify novel ketohexokinase (KHK) inhibitors. Biosystems 2015; 138: 39-52.
[http://dx.doi.org/10.1016/j.biosystems.2015.10.005] [PMID: 26521124]
[31]
Sakkiah S, Lee KW. Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors. Acta Pharmacol Sin 2012; 33(7): 964-78.
[http://dx.doi.org/10.1038/aps.2012.21] [PMID: 22684028]
[32]
World Alzheimer Report, London, Alzheimer Disease International Neurological disorder: public health challenges, Gene-va,World Health Organization 2009 2009; 2006.
[33]
Jotheeswaran AT, Williams JD, Prince MJ. The predictive validity of the 10/66 dementia diagnosis in Chennai, India: a 3-year follow-up study of cases identified at baseline. Alzheimer Dis Assoc Disord 2010; 24(3): 296-302.
[http://dx.doi.org/10.1097/WAD.0b013e3181d5e540] [PMID: 20473137]
[34]
Gross AL, Jones RN, Habtemariam DA, et al. Delirium and Long-term Cognitive Trajectory Among Persons With Dementia. Arch Intern Med 2012; 172(17): 1324-31.Sep 24.
[http://dx.doi.org/10.1001/archinternmed.2012.3203]
[35]
Shaffer JL, Petrella JR, Sheldon FC, et al. Alzheimer’s Disease Neuroimaging Initiative. Predicting cognitive decline in subjects at risk for Alzheimer disease by using combined cerebrospinal fluid, MR imaging, and PET biomarkers. Radiology 2013; 266(2): 583-91.
[http://dx.doi.org/10.1148/radiol.12120010] [PMID: 23232293]
[36]
Honjo K, Black SE, Verhoeff NP. Alzheimer’s disease, cerebrovascular disease, and the β-amyloid cascade. Can J Neurol Sci 2012; 39(6): 712-28.
[http://dx.doi.org/10.1017/S0317167100015547] [PMID: 23227576]
[37]
Mattson MP. Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci 2008; 1144: 97-112.
[http://dx.doi.org/10.1196/annals.1418.005] [PMID: 19076369]
[38]
Braak H, Del Tredici K. Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 2012; 25(6): 708-14.
[http://dx.doi.org/10.1097/WCO.0b013e32835a3432] [PMID: 23160422]
[39]
Revett TJ, Baker GB, Jhamandas J, Kar S. Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci 2013; 38(1): 6-23.
[http://dx.doi.org/10.1503/jpn.110190] [PMID: 22894822]
[40]
Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 2003; 43: 545-84.
[http://dx.doi.org/10.1146/annurev.pharmtox.43.100901.140248] [PMID: 12415125]
[41]
Wolfe MS. Gamma-secretase inhibition and modulation for Alzheimer’s disease. Curr Alzheimer Res 2008; 5(2): 158-64.
[http://dx.doi.org/10.2174/156720508783954767] [PMID: 18393800]
[42]
Jennings LD, Cole DC, Stock JR, et al. Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1′ substrate binding pocket. Bioorg Med Chem Lett 2008; 18(2): 767-71.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.043] [PMID: 18068983]
[43]
Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 2012; 120(Suppl. 1): 71-83.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07476.x] [PMID: 22122681]
[44]
Rao BN. Bioactive phytochemicals in Indian foods and their potential in health promotion and disease prevention. Asia Pac J Clin Nutr 2003; 12(1): 9-22.
[PMID: 12737006]
[45]
Hamburger M, Hostettmann K. Bioactivity in Plants: The Link between Phytochemistry and Medicine. Phytochemistry 1991; 30: 3864-74.
[http://dx.doi.org/10.1016/0031-9422(91)83425-K]
[46]
Tran N, In Kreutzer Jeffrey, DeLuca John, Caplan Bruce, Eds. Blood-brain barrier.Encyclopedia of Clinical Neuropsycholo-gy New York: Springer 2011; p. 426.
[47]
Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 2007; 22(5)E4
[http://dx.doi.org/10.3171/foc.2007.22.5.5] [PMID: 17613235]
[48]
Gasche Y, Soccal PM, Kanemitsu M, Copin JC. Front Biosci 2006 May 1; 11: 1289-301.
[49]
Zlokovic BV, Deane R, Sallstrom J, Chow N, Miano JM. Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol 2005; 15(1): 78-83.
[http://dx.doi.org/10.1111/j.1750-3639.2005.tb00103.x] [PMID: 15779240]
[50]
Deane R, Wu Z. Zlokovic. BV Stroke 2004; 35(11)(Suppl. 1): 2628-31.
[http://dx.doi.org/10.1161/01.STR.0000143452.85382.d1]
[51]
Sinha S, Anderson JP, Barbour R, et al. Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J,Lieberburg I, Power M, Tan H, Tatsuno Tung J, Schenk D, Seubert P,Suomensaari SM, Wang S, Walk-er D, Zhao J, McConlogue L, John V.. Purification and cloning of amyloid precursor protein beta-secretase
[52]
Hong L, Turner RT III, Koelsch G, Shin D, Ghosh AK, Tang J. Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry 2002; 41(36): 10963-7.
[http://dx.doi.org/10.1021/bi026232n] [PMID: 12206667]
[53]
Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290(5489): 150-3.
[http://dx.doi.org/10.1126/science.290.5489.150] [PMID: 11021803]
[54]
Martenyi F, Dean RA, Lowe S, et al. BACE inhibitor LY2886721 safety and central and peripheral PK and PD in healthy subjects (HSs). Alzheimers Dement 2012; 8: 583-P584.
[http://dx.doi.org/10.1016/j.jalz.2012.05.1588]
[55]
Forman M, Palcza J, Tseng J, et al. The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single- and multiple-dose administration. Alzheimers Dement 2012; 8: 704.
[http://dx.doi.org/10.1016/j.jalz.2012.05.1900]
[56]
Alexander R, Budd S, Russell M, et al. AZD3293 a novel bace1 inhibitor: safety tolerability and effects on plasma and CSF Ab peptides following single- and multiple-dose administration. Neurobiol Aging 2014; 35: S2.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.033]
[57]
Höglund K, Salter H, Zetterberg H, et al. Monitoring the Soluble Amyloid Precursor Protein Alpha (SAPPA) and Beta (SAPPB) fragments in plasma and CSF from healthy individuals treated with base inhibitor AZD3293 in a multiple ascending dose study, Pharmacokinetic and Pharmacodynamic correlate. Alzheimers Dement 2014; 10: 447.
[http://dx.doi.org/10.1016/j.jalz.2014.05.605]
[58]
Lai R, Albala B, Kaplow JM, Aluri J, Yen M, Satlin A. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimers Dement 2012; 8: 96.
[http://dx.doi.org/10.1016/j.jalz.2012.05.237]
[59]
Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther 2014; 6(9): 89.
[60]
Eroglu E, Türkmen H. A DFT-based quantum theoretic QSAR study of aromatic and heterocyclic sulfonamides as carbonic anhydrase inhibitors against isozyme, CA-II. J Mol Graph Model 2007; 26(4): 701-8.
[http://dx.doi.org/10.1016/j.jmgm.2007.03.015] [PMID: 17493855]
[61]
Akhtar A, Amir A, Hussain W, Ghaffar A, Rasool N. In Silico Computations of Selective Phytochemicals as Potential Inhibitors Against Major Biological Targets of Diabetes Mellitus. Curr Comput Aided Drug Des 2019; 15(5): 401-8.
[62]
Hussain W, Qaddir I, Mahmood S, Rasool N. In silico targeting of non-structural 4B protein from dengue virus 4 with spiropyrazolopyridone: study of molecular dynamics simulation, ADMET and virtual screening. Virusdisease 2018; 29(2): 147-56.

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