Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In-silico Studies and Biological Activity of Potential BACE-1 Inhibitors

Author(s): Richa Arya*, Sarvesh Paliwal, Satya P. Gupta, Swapnil Sharma, Kirtika Madan, Achal Mishra, Kanika Verma and Neha Chauhan

Volume 24, Issue 5, 2021

Published on: 18 September, 2020

Page: [729 - 736] Pages: 8

DOI: 10.2174/1386207323999200918151331

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Alzheimer’s disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP).

Objective: The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease.

Methods: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds.

Results: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions.

Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1μM.

Keywords: BACE-1, docking, in-silico, pharmacophore, secretase, secretase, BACE-1.

« Previous Next »
[1]
Selkoe, D.J. The molecular pathology of Alzheimer’s disease. Neuron, 1991, 6(4), 487-498.
[http://dx.doi.org/10.1016/0896-6273(91)90052-2] [PMID: 1673054]
[2]
Lyketsos, C.G.; Carrillo, M.C.; Ryan, J.M.; Khachaturian, A.S.; Trzepacz, P.; Amatniek, J.; Cedarbaum, J.; Brashear, R.; Miller, D.S. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement., 2011, 7(5), 532-539.
[http://dx.doi.org/10.1016/j.jalz.2011.05.2410] [PMID: 21889116]
[3]
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement., 2016, 12(4), 459-509.
[http://dx.doi.org/10.1016/j.jalz.2016.03.001] [PMID: 27570871]
[4]
LaFerla, F.M.; Green, K.N.; Oddo, S. Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci., 2007, 8(7), 499-509.
[http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]
[5]
Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A.; Tang, J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl. Acad. Sci. USA, 2000, 97(4), 1456-1460.
[http://dx.doi.org/10.1073/pnas.97.4.1456] [PMID: 10677483]
[6]
Roberds, S.L.; Anderson, J.; Basi, G.; Bienkowski, M.J.; Branstetter, D.G.; Chen, K.S.; Freedman, S.B.; Frigon, N.L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K.E.; Kawabe, T.T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N.F.; Power, M.; Robertson, D.W.; Schenk, D.; Schoor, M.; Shopp, G.M.; Shuck, M.E.; Sinha, S.; Svensson, K.A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet., 2001, 10(12), 1317-1324.
[http://dx.doi.org/10.1093/hmg/10.12.1317] [PMID: 11406613]
[7]
Rajamani, R.; Reynolds, C.H. Modeling the protonation states of the catalytic aspartates in β-secretase. J. Med. Chem., 2004, 47(21), 5159-5166.
[http://dx.doi.org/10.1021/jm049817j] [PMID: 15456259]
[8]
Kumalo, H.M.; Bhakat, S.; Soliman, M.E. Investigation of flap flexibility of β-secretase using molecular dynamic simulations. J. Biomol. Struct. Dyn., 2016, 34(5), 1008-1019.
[http://dx.doi.org/10.1080/07391102.2015.1064831] [PMID: 26208540]
[9]
Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(9), 89.
[http://dx.doi.org/10.1186/s13195-014-0089-7] [PMID: 25621019]
[10]
Hung, S.Y.; Fu, W.M. Drug candidates in clinical trials for Alzheimer’s disease. J. Biomed. Sci., 2017, 24(1), 47.
[http://dx.doi.org/10.1186/s12929-017-0355-7] [PMID: 28720101]
[11]
Lopez, O.L.; Becker, J.T.; Wahed, A.S.; Saxton, J.; Sweet, R.A.; Wolk, D.A.; Klunk, W.; Dekosky, S.T. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J. Neurol. Neurosurg. Psychiatry, 2009, 80(6), 600-607.
[http://dx.doi.org/10.1136/jnnp.2008.158964] [PMID: 19204022]
[12]
Prado-Prado, F.; Escobar-Cubiella, M.; Garcia-Mera, X. Review of bioinformatics and QSAR studies of β-secretase inhibitors. Curr. Bioinform., 2016, 6(1), 3-15.
[http://dx.doi.org/10.2174/157489311795222428]
[13]
Gupta, S.P. QSAR studies on hydroxamic acids: a fascinating family of chemicals with a wide spectrum of activities. Chem. Rev., 2015, 115(13), 6427-6490.
[http://dx.doi.org/10.1021/cr500483r] [PMID: 26024019]
[14]
Mittal, A.; Paliwal, S.; Sharma, M.; Singh, A.; Sharma, S.; Yadav, D. Pharmacophore based virtual screening, molecular docking and biological evaluation to identify novel PDE5 inhibitors with vasodilatory activity. Bioorg. Med. Chem. Lett., 2014, 24(14), 3137-3141.
[http://dx.doi.org/10.1016/j.bmcl.2014.05.004] [PMID: 24856068]
[15]
Arya, R.; Gupta, S.P.; Paliwal, S.; Sharma, S.; Madan, K.; Chauhan, M. Pharmacophore modeling and docking studies to investigate potential leads for the development of Beta-secretase APP cleavage enzyme-1 (BACE-1) inhibitors. Lett. Drug Des. Discov., 2019, 16(7), 775-784.
[http://dx.doi.org/10.2174/1570180815666181023110736]
[16]
Aouidate, A.; Ghaleb, A.; Ghamali, M.; Chtita, S.; Choukrad, M.B.; Sbai, A.; Bouachrine, M.; Lakhlifi, T. Combined 3D-QSAR and molecular docking study on 7, 8-dialkyl-1, 3-diaminopyrrolo-[3, 2-f] quinazoline series compounds to understand the binding mechanism of DHFR inhibitors. J. Mol. Struct., 2017, 1139, 319-327.
[http://dx.doi.org/10.1016/j.molstruc.2017.03.039]
[17]
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(1), 414-417.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.116] [PMID: 18023580]
[18]
Iserloh, U.; Pan, J.; Stamford, A.W.; Kennedy, M.E.; Zhang, Q.; Zhang, L.; Parker, E.M.; McHugh, N.A.; Favreau, L.; Strickland, C.; Voigt, J. Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor. Bioorg. Med. Chem. Lett., 2008, 18(1), 418-422.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.053] [PMID: 17980584]
[19]
Arya, R.; Gupta, S.; Paliwal, S.; Kesar, S.; Mishra, A.; Prabhakar, Y.S. QSAR and molecular modeling studies on a series of pyrrolidine analogs acting as BACE-1 inhibitors. Lett. Drug Des. Discov., 2019, 16(7), 746-760.
[http://dx.doi.org/10.2174/1570180815666180627124422]
[20]
Yang, S.Y. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov. Today, 2010, 15(11-12), 444-450.
[http://dx.doi.org/10.1016/j.drudis.2010.03.013] [PMID: 20362693]
[21]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[22]
López-Camacho, E.; García-Godoy, M.J.; García-Nieto, J.; Nebro, A.J.; Aldana-Montes, A.J. A new multi-objective approach for molecular docking based on RMSD and binding energy International Conference on Algorithms for Computational Biology, 2016, pp. 65-77.
[http://dx.doi.org/10.1007/978-3-319-38827-4_6]
[23]
Gramatica, P.; Sangion, A. A historical excursus on the statistical validation parameters for QSAR models: A clarification concerning metrics and terminology. J. Chem. Inf. Model., 2016, 56(6), 1127-1131.
[http://dx.doi.org/10.1021/acs.jcim.6b00088] [PMID: 27218604]
[24]
Marcin, L.R.; Higgins, M.A.; Zusi, F.C.; Zhang, Y.; Dee, M.F.; Parker, M.F.; Muckelbauer, J.K.; Camac, D.M.; Morin, P.E.; Ramamurthy, V.; Tebben, A.J.; Lentz, K.A.; Grace, J.E.; Marcinkeviciene, J.A.; Kopcho, L.M.; Burton, C.R.; Barten, D.M.; Toyn, J.H.; Meredith, J.E.; Albright, C.F.; Bronson, J.J.; Macor, J.E.; Thompson, L.A. Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1. Bioorg. Med. Chem. Lett., 2011, 21(1), 537-541.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.079] [PMID: 21078556]
[25]
Madan, K.; Verma, A.N.; Paliwal, S.K.; Yadav, D.; Sharma, S.; Sharma, M. Pharmacophore modeling and database mining to identify novel lead compounds active against the disease stage of Trypanosomiasis in the central nervous system. Int. J. Nutr. Pharmacol. Neurol. Dis., 2018, 8(1), 16-31.
[26]
Kumar, A.; Zhang, K.Y.J. Hierarchical virtual screening approaches in small molecule drug discovery. Methods, 2015, 71, 26-37.
[http://dx.doi.org/10.1016/j.ymeth.2014.07.007] [PMID: 25072167]
[27]
Bhargavi, M.V.; Shashikala, P.; Sumakanth, M. Krishna, C.; Synthesis, molecular docking, analgesic, and anti-inflammatory activities of new 1, 2, 4-oxadiazolo-sulfonamides. Russ. J. Gen. Chem., 2018, 88(4), 804-811.
[http://dx.doi.org/10.1134/S1070363218040278]
[28]
Chakraborty, S.; Ramachandran, B.; Basu, S. Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition. Mol. Biosyst., 2014, 10(10), 2684-2692.
[http://dx.doi.org/10.1039/C4MB00307A] [PMID: 25088750]
[29]
Ju, Y.; Li, Z.; Deng, Y.; Tong, A.; Zhou, L.; Luo, Y. Identification of novel BACE1 inhibitors by combination of pharmacophore modeling, structure-based design and in vitro assay, Curr. Comput. Aided. Curr Comput Aided Drug Des, 2016, 12(1), 73-82.
[http://dx.doi.org/10.2174/1573409912666160222113103] [PMID: 26899408]
[30]
Manoharan, P.; Chennoju, K.; Ghoshal, N. Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P-glycoprotein binding property. J. Biomol. Struct. Dyn., 2018, 36(1), 262-276.
[http://dx.doi.org/10.1080/07391102.2016.1276477] [PMID: 28081663]
[31]
Pfeiffenberger, E.; Chaleil, R.A.; Moal, I.H.; Bates, P.A. A machine learning approach for ranking clusters of docked protein-protein complexes by pairwise cluster comparison. Proteins, 2017, 85(3), 528-543.
[http://dx.doi.org/10.1002/prot.25218] [PMID: 27935158]
[32]
Al-Nadaf, A.H.; Taha, M.O. Identification of small molecule memapsin inhibitors via computation-based virtual screening. Adv. Pharmacol. Pharm., 2015, 3(3), 53-63.
[http://dx.doi.org/10.13189/app.2015.030301]

Rights & Permissions Print Cite
Article Metrics
25
1
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy