QSAR and Molecular Modeling Studies on a Series of Pyrrolidine Analogs Acting as BACE-1 Inhibitors

Author(s): Richa Arya, Satya Prakash Gupta*, Sarvesh Paliwal, Seema Kesar, Achal Mishra, Yenamandra Subrahmanya Prabhakar.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: β-Site amyloidal precursor protein (APP) cleavage enzyme (BACE-1) is reported as prime cause for progession of Alzheimer’s disease (AD). It is a form of dementia characterized by degeneration of neurones in brain. Therefore, attempts have been made to find potent inhibitors of this enzyme.

Methods: The paper presents an division-based 2D quantitative structure-activity relationship (QSAR) study on a series of BACE-1 inhibitors to analyse the structural features that may be important to increase the potency of the compounds.

Results: The study led to predict some potential leads for the development of potent inhibitors of BACE-1. One of the molecule with pyrrolidine and pyrrolidinone substitutions exhibited drugreceptor interactions comparable with reference drug.

Conclusion: The hydrogen-bond interactions between the molecules and the receptor basically control the BACE-1 inhibition activity of the compounds.

Keywords: Beta-secretase 1 (BACE-1) inhibitors, beta-site APP cleaving enzyme 1, Quantitative structure-activity relationship (QSAR), MLR, Alzheimer's disease.

[1]
Jalbert, J.J.; Daiello, L.A.; Lapane, K.L. Dementia of the Alzheimer type. Epidemiol. Rev., 2008, 30, 15-34.
[2]
World Alzheimer Report 2016: Improving healthcare for people living with dementia: Coverage, quality and costs now and in the future. 03 November 2016. www.alz.co.uk/research/world-report-2016 (Accessed November 10, 2017).
[3]
Vickers, J.C.; Dickson, T.C.; Adlard, P.A.; Saunders, H.L.; King, C.E.; McCormack, G. The cause of neuronal degeneration in Alzheimer’s disease. Prog. Neurobiol., 2000, 60, 139-165.
[4]
Small, S.A.; Gandy, S. Sorting through the cell biology review of Alzheimer’s disease: Intracellular pathways to pathogenesis. Neuron, 2006, 52, 15-31.
[5]
Ballatore, C.; Lee, V.M.; Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci., 2007, 8, 663-672.
[6]
Ghosh, A.K.; Gemm, S.; Tang, J. β-Secretase as a therapeutic target for Alzheimer’s disease. Neurotherapeutics, 2008, 5, 399-408.
[7]
Vassar, R.; Kandalepas, P.C. The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimers Res. Ther., 2011, 3, 20.
[8]
Golbraikh, A.; Shen, M.; Xiao, Z.; Xiao, Y.D.; Lee, K.H.; Tropsha, A. Rational selection of training and test sets for the development of validated QSAR models. Comput. Aided. Mol. Des., 2003, 17, 241-253.
[9]
Paliwal, S.K.; Verma, A.N; Paliwal, S. Structure-activity relationship analysis of cationic 2-phenylbenzofurans as potent anti-trypanosomal agents: A multivariate statistical approach. Q.C.S, 2009, 28, 1367-1375.
[10]
Kennedy, M.E.; Stamford, A.W.; Chen, X.; Cox, K.; Cumming, J.N.; Dockendorf, M.F.; Egan, M.; Ereshefsky, L.; Hodgson, R.A.; Hyde, L.A.; Jhee, S.; Kleijn, H.J.; Kuvelkar, R.L.W.; Mattson, B.A.; Mei, H.; Palcza, J.; Scott, J.D.; Tanen, M.; Troyer, M.D.; Tseng, J.L.; Stone, J.A.; Parker, E.M.; Forman, M.S. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci. Transl. Med., 2016, 8, 363ra150.
[11]
Eketjäll, S.; Janson, J.; Kaspersson, K.; Bogstedt, A.; Jeppsson, F.; Fälting, J.; Haeberlein, S.B.; Kugler, A.R.; Alexander, R.C.; Cebers, G. AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis., 2016, 50, 1109-1123.
[12]
Sims, J.R.; Selzler, K.J.; Downing, A.M.; Willis, B.A.; Aluise, C.D.; Zimmer, J.; Bragg, S.; Andersen, S.; Ayan-Oshodi, M.; Liffick, E.; Eads, J.; Wessels, A.M.; Monk, S.; Schumi, J.; Mullen, J. Development review of the BACE1 inhibitor lanabecestat (AZD3293/LY3314814). J. Prev. Alzheimers Dis., 2017, 4, 247-254.
[13]
Mullard, A. BACE inhibitor bust in Alzheimer trial. Nat. Rev. Drug Discov., 2017, 16, 155.
[14]
Iserloh, U.; Wu, Y.; Cumming, J.N.; Pan, J.; Wang, L.Y.; Stamford, A.W.; Kennedy, M.E.; Kuvelkar, R.; Chen, X.; Parker, E.M.; Strickland, C.; Voigt, J. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 414-417.
[15]
Iserloh, U.; Wu, Y.; Cumming, J.N.; Pang, J.; Wang, L.Y.; Stamford, A.W.; Kennedy, M.E.; Kuvelkar, R.; Chen, X.; Parker, E.M.; Strickland, C.; Voigt, J. Discovery of an orally efficaceous 4-phenoxypyrrolidine-based. BACE-1 inhibitor. Bioorg. Med. Chem. Lett., 2008, 18, 418-422.
[16]
Ruiz, P.; Myshkin, E.; Quigley, P.; Faroon, O.; Wheeler, J.S.; Mumtaz, M.M.; Brennan, R.J. Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: A QSAR comparative analysis. SAR QSAR Environ. Res., 2013, 24, 393-416.
[17]
Roy, K.D. RNA review on principles, theory and practices of 2D-QSAR. Curr. Drug Metab., 2014, 15, 346-379.
[18]
Castilho, M.S.; Guido, R.V.C.; Andricopulo, A.D. Classical and hologram QSAR studies on a series of tacrine derivatives as butyrylcholinesterase inhibitors. Lett. Drug Des. Discov., 2007, 4, 106-113.
[19]
Chang, H.J.; Kim, H.J.; Chun, H.S. Quantitative structure-activity relationship (QSAR) for neuroprotective activity of terpenoid. Life Sci., 2007, 80, 835-841.
[20]
Patel, D.K.; Patel, N.M. QSAR analysis of aminoquinoline analogues as MCH1 receptor antagonist. J. Sci. Res., 2009, 1, 594-605.
[21]
Luco, J.M.; Ferretti, F.H. QSAR based on multiple linear regression and PLS methods for the anti-HIV activity of a large group of HEPT derivatives. J. Chem. Inf. Comput. Sci., 1997, 37, 392-401.
[22]
Panda, S.S.; Liaqat, S.; Girgis, A.S.; Samir, A.; Hall, C.D.; Katritzky, A.R. Novel antibacterial active quinolone-fluoroquinolone conjugates and 2D-QSAR studies. Bioorg. Med. Chem. Lett., 2015, 25, 3816-3821.
[23]
Gramatica, P. Principles of QSAR models validation: Internal and external. QSAR Comb. Sci., 2007, 26, 694-701.
[24]
Eriksson, L.; Jaworska, J.; Gramatica, P. Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ. Health Perspect., 2003, 111, 1361-1375.
[25]
Weaver, S.; Gleeson, M.P. The importance of the domain of applicability in QSAR modeling. J. Mol. Graph. Model., 2008, 26, 1315-132.
[26]
Sharma, A.; Gupta, S.P.; Siddiqui, A.A. A QSAR study on a series of thiourea derivatives acting as anti-hepatitis C virus agents. Indian J. Biochem. Biophys., 2013, 50, 278-283.
[27]
Gupta, R.A.; Gupta, A.K.; Soni, L.K.; Kaskhedikar, S.G. 2-(pyrazin-2-yloxy)acetohydrazide analogs QSAR study: An insight into the structural basis of antimycobacterial activity. Chem. Biol. Drug Des., 2010, 76, 441-450.
[28]
Sabbah, D.A.; Zhong, H.A. Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies. J. Mol. Graph. Model., 2016, 68, 206-215.
[29]
Masand, N.; Gupta, S.P.; Khosa, R.L.; Patil, V.M. Heterocyclic secretase inhibitors for the treatment of alzheimer’s disease: An overview. Cent. Nerv. Syst. Agents Med. Chem., 2017, 17, 3-25.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 7
Year: 2019
Page: [746 - 760]
Pages: 15
DOI: 10.2174/1570180815666180627124422
Price: $58

Article Metrics

PDF: 21
HTML: 3