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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Identification of Potent Bioactive Molecules Against NMDA Receptor and Tau Protein by Molecular Docking Approach

Author(s): Prachi Parvatikar*, Shrilaxmi Bagali, Surekha Hippargi, Pankaj K. Singh, Shashi Bala Singh, M.S. Biradar, Aravind V. Patil and Kusal K. Das

Volume 20, Issue 8, 2023

Published on: 06 October, 2022

Page: [1031 - 1039] Pages: 9

DOI: 10.2174/1570180819666220616142153

Price: $65

Abstract

Introduction: N-methyl-d-aspartate receptor (NMDAR) and tau protein play an important role in neuronal death due to cerebral ischemia or ischemic stroke. Unfortunately, no drug has been discovered except tissue plasminogen activator (tPA) to fight against ischemic stroke. Virtual high throughput screening to find out possibilities of bioactive molecules to target NMDAR and tau protein to treat ischemic stroke may be an option for drug discovery.

Objective: The current study aimed to assess the molecular interaction of some bioactive molecules with NMDAR and tau protein in silico to incriminate ischemic stroke.

Methods: A computational method based on ligand-protein interaction technique has been used in the present study to identify the therapeutic potential of some bioactive molecules for the possible treatment of ischemic stroke. For this purpose, 50 bioactive molecules were screened and docking analysis was performed for two target proteins, NMDAR and tau protein. In this study, for each protein target, the best poses were identified based on binding energy and inhibition constant. Different pharmacological properties of selected bioactive molecules were also analyzed to determine their absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties in silico. All were found in the acceptable range and followed Lipinski’s rule.

Results: In the present study of the 50 screened bioactive molecules, top 10 molecules have been identified, of which best two bioactive molecules such as gossypin, viniferin have been predicted to be potential neuroprotective agents against cerebral ischemia induced alteration of NMDAR and tau protein functional integrities.

Conclusion: Gossypin’ was the best bioactive compound interacting with NMDAR and tau protein.

Keywords: NMDA receptor, tau protein, ischemic stroke, bioactive molecules

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[1]
Donnan, G.A.; Fisher, M.; Macleod, M.; Davis, S.M. Stroke. Lancet, 2008, 371(9624), 1612-1623.
[http://dx.doi.org/10.1016/S0140-6736(08)60694-7] [PMID: 18468545]
[2]
Chen, X.; Jiang, H. Tau as a potential therapeutic target for ischemic stroke. Aging (Albany NY), 2019, 11(24), 12827-12843.
[http://dx.doi.org/10.18632/aging.102547] [PMID: 31841442]
[3]
Dirnagl, U.; Iadecola, C.; Moskowitz, M.A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci., 1999, 22(9), 391-397.
[http://dx.doi.org/10.1016/S0166-2236(99)01401-0] [PMID: 10441299]
[4]
Krueger, B.A.; Weil, T.; Schneider, G. Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists. J. Comput. Aided Mol. Des., 2009, 23(12), 869-881.
[http://dx.doi.org/10.1007/s10822-009-9304-1] [PMID: 19890609]
[5]
Goedert, M.; Spillantini, M.G.; Potier, M.C.; Ulrich, J.; Crowther, R.A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J., 1989, 8(2), 393-399.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb03390.x] [PMID: 2498079]
[6]
Hong, X.P.; Peng, C.X.; Wei, W.; Tian, Q.; Liu, Y.H.; Yao, X.Q.; Zhang, Y.; Cao, F.Y.; Wang, Q.; Wang, J.Z. Essential role of tau phosphorylation in adult hippocampal neurogenesis. Hippocampus, 2010, 20(12), 1339-1349.
[http://dx.doi.org/10.1002/hipo.20712] [PMID: 19816983]
[7]
Yadav, R.N.S.; Agarwala, M. Phytochemical analysis of some medicinal plants. J. Phytol., 2011.
[8]
Studio, D. Discovery Studio; Accelrys, 2008.
[9]
Guex, N.; Peitsch, M.C. SWISS MODEL and the Swiss Pdb Viewer: an environment for comparative protein modeling. Electrophoresis, 1997, 18(15), 2714-2723.
[10]
Laskowski, R.A.; Jabłońska, J.; Pravda, L.; Vařeková, R.S.; Thornton, J.M. PDBsum: Structural summaries of PDB entries. Protein Sci., 2018, 27(1), 129-134.
[http://dx.doi.org/10.1002/pro.3289] [PMID: 28875543]
[11]
Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.; Agarwal, S.M. NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database. Nucleic Acids Res., 2013, 41(Database issue), D1124-D1129.
[http://dx.doi.org/10.1093/nar/gks1047] [PMID: 23203877]
[12]
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(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[13]
Huey, R.; Morris, G.M.; Forli, S. Using AutoDock 4 and AutoDock vina with AutoDockTools: a tutorial. Scripps Research Institute Molecular Graphics Laboratory., 2012, 10550, 92037.
[14]
Ortiz, C.L.D.; Completo, G.C.; Nacario, R.C.; Nellas, R.B. Potential inhibitors of galactofuranosyltransferase 2 (GlfT2): Molecular docking, 3D-QSAR, and in silico ADMETox Studies. Sci. Rep., 2019, 9(1), 17096.
[http://dx.doi.org/10.1038/s41598-019-52764-8] [PMID: 31745103]
[15]
Sahin, K. Investigation of novel indole-based HIV-1 protease inhibitors using virtual screening and text mining. J. Biomol. Struct. Dyn., 2021, 39(10), 3638-3648.
[http://dx.doi.org/10.1080/07391102.2020.1775121] [PMID: 32496942]
[16]
Lee, H.M.; Kim, Y. Drug repurposing is a new opportunity for developing drugs against neuropsychiatric disorders. Schizophr. Res. Treatment, 2016, 2016, 6378137.
[http://dx.doi.org/10.1155/2016/6378137] [PMID: 27073698]
[17]
Szydlowska, K.; Tymianski, M. Calcium, ischemia and excitotoxicity. Cell Calcium, 2010, 47(2), 122-129.
[http://dx.doi.org/10.1016/j.ceca.2010.01.003] [PMID: 20167368]
[18]
Kunnumakkara, A.B.; Nair, A.S.; Ahn, K.S.; Pandey, M.K.; Yi, Z.; Liu, M.; Aggarwal, B.B. Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis. Blood, 2007, 109(12), 5112-5121.
[http://dx.doi.org/10.1182/blood-2007-01-067256] [PMID: 17332240]
[19]
Richard, T.; Papastamoulis, Y.; Waffo-Teguo, P.; Monti, J.P. 3D NMR structure of a complex between the amyloid beta peptide (1-40) and the polyphenol ε-viniferin glucoside: implications in Alzheimer’s disease. Biochim. Biophys. Acta, 2013, 1830(11), 5068-5074.
[http://dx.doi.org/10.1016/j.bbagen.2013.06.031] [PMID: 23830862]
[20]
Lai, T.W.; Shyu, W.C.; Wang, Y.T. Stroke intervention pathways: NMDA receptors and beyond. Trends Mol. Med., 2011, 17(5), 266-275.
[http://dx.doi.org/10.1016/j.molmed.2010.12.008] [PMID: 21310659]
[21]
Tymianski, M.; Charlton, M.P.; Carlen, P.L.; Tator, C.H. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J. Neurosci., 1993, 13(5), 2085-2104.
[http://dx.doi.org/10.1523/JNEUROSCI.13-05-02085.1993] [PMID: 8097530]
[22]
Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch., 2010, 460(2), 525-542.
[http://dx.doi.org/10.1007/s00424-010-0809-1] [PMID: 20229265]
[23]
Xu, J.; Kurup, P.; Zhang, Y.; Goebel-Goody, S.M.; Wu, P.H.; Hawasli, A.H.; Baum, M.L.; Bibb, J.A.; Lombroso, P.J. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J. Neurosci., 2009, 29(29), 9330-9343.
[http://dx.doi.org/10.1523/JNEUROSCI.2212-09.2009] [PMID: 19625523]
[24]
Violet, M.; Delattre, L.; Tardivel, M.; Sultan, A.; Chauderlier, A.; Caillierez, R.; Talahari, S.; Nesslany, F.; Lefebvre, B.; Bonnefoy, E.; Buée, L.; Galas, M.C. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front. Cell. Neurosci., 2014, 8, 84.
[http://dx.doi.org/10.3389/fncel.2014.00084] [PMID: 24672431]
[25]
Bi, M.; Gladbach, A.; van Eersel, J.; Ittner, A.; Przybyla, M.; van Hummel, A.; Chua, S.W.; van der Hoven, J.; Lee, W.S.; Müller, J.; Parmar, J.; Jonquieres, G.V.; Stefen, H.; Guccione, E.; Fath, T.; Housley, G.D.; Klugmann, M.; Ke, Y.D.; Ittner, L.M. Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat. Commun., 2017, 8(1), 473.
[http://dx.doi.org/10.1038/s41467-017-00618-0] [PMID: 28883427]
[26]
Trojanowski, J.Q.; Schuck, T.; Schmidt, M.L.; Lee, V.M. Distribution of tau proteins in the normal human central and peripheral nervous system. J. Histochem. Cytochem., 1989, 37(2), 209-215.
[http://dx.doi.org/10.1177/37.2.2492045] [PMID: 2492045]
[27]
Pluta, R.; Bogucka-Kocka, A.; Ułamek-Kozioł, M.; Bogucki, J.; Januszewski, S.; Kocki, J.; Czuczwar, S.J. Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer’s phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer’s disease. Pharmacol. Rep., 2018, 70(5), 881-884.
[http://dx.doi.org/10.1016/j.pharep.2018.03.004]

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