MOLECULAR DOCKING STUDIES OF SOME N-AMIDOALKYLATED DERIVATIVES OF 2-AMINO-1,3,4-OXADIAZOLE AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β
Alzheimer's disease is a neurodegenerative disease characterized by pathological features of neurofibrillary tangles and β-amyloid plaques in the cerebral cortex. In Alzheimer's disease, tau protein undergoes excess phosphorylation, due to which its threads begin to merge and form neurofibrillary tangles within nerve cells. It has been shown that glycogen synthase kinase-3β is a key factor in the phosphorylation of tau protein, its increased activity leading to pathologies of neurofibrillary tangles and, consequently, to neurodegenerative changes in the brain. In this connection, the search for effective inhibitors of GSK-3β is a very important and urgent task, for their further use in the treatment of Alzheimer's disease.
Aim of research.The aim of this study is to search new inhibitors of GSK-3β among N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole by molecular docking methods.
Materials and methods. We have carried out geometry optimization of analyzed structures within PM3 semi-empirical method, and GSK-3β molecular docking using software ArgusLab 4.0.1. The three-dimensional crystal structure of co-crystallizer GSK-3β and inhibitor has been loaded from the data bank of protein molecules (PDB ID: 3F7Z).
Results. In this study it has been shown that the structures being studied mainly form stronger complexes with the enzyme compared to the known inhibitor. Based on the results of molecular docking, the compounds leaders N-(((5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)amino)methyl)benzamide and 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide have been chosen. The structures of the compounds leaders have been tested for compliance with Lipinski criteria.
Conclusions. Proposed compounds leaders can be recommended for further studies in the treatment of Alzheimer's disease. Despite the good results obtained in silico analysis, it is mandatory to perform biological tests in vitro and in vivo.
Hasegawa, M. (2016). Molecular Mechanisms in the Pathogenesis of Alzheimer’s disease and Tauopathies-Prion-Like Seeded Aggregation and Phosphorylation. Biomolecules, 6 (2), 24–36. doi: http://doi.org/10.3390/biom6020024
Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X. et. al. (2005). Tau pathology in Alzheimer disease and other tauopathies. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1739 (2-3), 198–210. doi: http://doi.org/10.1016/j.bbadis.2004.09.008
Canter, R. G., Penney, J., Tsai, L.-H. (2016). The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature, 539 (7628), 187–196. doi: http://doi.org/10.1038/nature20412
Chun, W., Johnson, G. V. (2007). The role of tau phosphorylation and cleavage in neuronal cell death. Frontiers in Bioscience, 12 (1), 733–756. doi: http://doi.org/10.2741/2097
Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M. et. al. (1992). Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. The Journal of Biological Chemistry, 267 (15), 10897–10901.
Pei, J.-J., Tanaka, T., Tung, Y.-C., Braak, E., Iqbal, K., Grundke-Iqbal, I. (1997). Distribution, Levels, and Activity of Glycogen Synthase Kinase-3 in the Alzheimer Disease Brain. Journal of Neuropathology and Experimental Neurology, 56 (1), 70–78. doi: http://doi.org/10.1097/00005072-199701000-00007
Pei, J.-J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., Cowburn, R. F. (1999). Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes. Journal of Neuropathology & Experimental Neurology, 58 (9), 1010–1019. doi: http://doi.org/10.1097/00005072-199909000-00011
Licht-Murava, A., Paz, R., Vaks, L., Avrahami, L., Plotkin, B., Eisenstein, M., Eldar-Finkelman, H. (2016). A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Science Signaling, 9 (454), ra110. doi: http://doi.org/10.1126/scisignal.aah7102
Palomo, V., Martinez, A. (2016). Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014–2015). Expert Opinion on Therapeutic Patents, 27 (6), 657–666. doi: http://doi.org/10.1080/13543776.2017.1259412
Saitoh, M., Kunitomo, J., Kimura, E., Hayase, Y., Kobayashi, H., Uchiyama, N. et. al. (2009). Design, synthesis and structure–activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β. Bioorganic & Medicinal Chemistry, 17 (5), 2017–2029. doi: http://doi.org/10.1016/j.bmc.2009.01.019
Young, D. C. (2009). Computational drug design. New Jersey: John Wiley & Sons, Inc., Hoboken, 307.
Zadorozhnii, P. V., Kiselev, V. V., Kharchenko, A. V. (2015). Synthesis of Nitrogen-Containing Heterocycles Based on N-(Isothiocyanatoalkyl)carboxamides. Modern Directions in Chemistry, Biology, Pharmacy and Biotechnology. Lviv: Lviv Polytechnic Publishing House, 212–219.
Chernous, S. Y., Kharchenko, A. V., Kiselev, V. V. (2007). N-(2,2,2-Trichloro-1-isothiocyanatoethyl)amides of the carboxylic acids in the syntheses of nitrogen-containing heterocyclic compounds. Voprosy khimii i khimicheskoy tekhnologii, 6, 59–61.
Zadorozhnii, P. V., Kiselev, V. V., Chernous, S. Y., Kharchenko, A. V., Okhtina, O. V. (2012). Synthesis of amidoalkylation 2-amino-1,3,4-oxadiazole derivatives. Voprosy khimii i khimicheskoy tekhnologii, 6, 30–32.
Thompson, M. (2004). ArgusLab 4.0.1. Planaria software LLC. Seattle. Available at: http://www.arguslab.com
Zadorozhnii, P. V., Kiselev, V. V., Titova, A. E., Kharchenko, A. V., Pokotylo, I. O., Okhtina, O. V. (2017). Molecular Docking Studies of N-5-Aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacetamidines as Inhibitors of Enoyl-ACP Reductase Mycobacterium tuberculosis. Research Journal of Pharmacy and Technology, 10 (4), 1091–1097. doi: http://doi.org/10.5958/0974-360x.2017.00198.6
Zadorozhnii, P. V., Kiselev, V. V., Teslenko, N. O., Kharchenko, A. V., Pokotylo, I. O., Okhtina, O. V., Kryshchyk, O. V. (2017). In Silico Prediction and Molecular Docking Studies of N-Amidoalkylated Derivatives of 1, 3, 4-Oxadiazole as COX-1 and COX-2 Potential Inhibitors. Research Journal of Pharmacy and Technology, 10 (11), 3957–3963. doi: http://doi.org/10.5958/0974-360x.2017.00718.1
Wang, R., Lai, L., Wang, S. (2002). Further development and validation of empirical scoring functions for structure-based binding affinity prediction. Journal of Computer-Aided Molecular Design, 16 (1), 11–26. doi: http://doi.org/10.1023/a:1016357811882
DeLano, W. L. (2003). The PyMOL Molecular Graphics System. Scientific: Palo Alto. Available at: http://www.pymol.org
Ferreira, L., dos Santos, R., Oliva, G., Andricopulo, A. (2015). Molecular Docking and Structure-Based Drug Design Strategies. Molecules, 20 (7), 13384–13421. doi: http://doi.org/10.3390/molecules200713384
Juszczak, M., Walczak, K., Langner, E., Karpińska, M., Matysiak, J., Rzeski, W. (2013). Neuroprotective activity of 2-amino-1,3,4-thiadiazole derivative 4BrABT an in vitro study. Annals of Agricultural and Environmental Medicine, 20 (3), 575–579.
Saeedi, M., Safavi, M., Karimpour-Razkenari, E., Mahdavi, M., Edraki, N., Moghadam, F. H. et. al. (2017). Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease. Bioorganic Chemistry, 70, 86–93. doi: http://doi.org/10.1016/j.bioorg.2016.11.011
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