IDENTIFICATION OF NOVEL GLYCOGEN SYNTHASE KINASE-3Β INHIBITOR THROUGH COMBINED SHAPE-BASED SCREENING AND MOLECULAR DOCKING APPROACH
Abstract
Glycogen synthase kinase-3β (GSK-3β) is an important class of therapeutic drug target currently receiving wide attention. In our computational approach, shape-based similarity search was used to screen the SPECS database, based on the shape of Tideglusib molecule; a known GSK-3β inhibitor. The resulting virtual hits were applied for docking studies on the known binding pockets of GSK-3β. A novel compound [7,10-dioxo-4,5-dihydro-7H,10H-pyrano[3,2,1-ij]quinolin-8-yl acetate] proposed from docking results in the substrate site of GSK-3β was found to have inhibitory activity (IC50) above 100μM concentration in ADP-GloTM Kinase assay. This communication aims to put forward in identifying newer hit on GSK-3β target via virtual screening approach.
Keywords:
Glycogen synthase kinase-3β, Tideglusib, Virtual screening, ADP-GloTM Kinase assay.DOI
https://doi.org/10.25004/IJPSDR.2017.090308References
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12. Tideglusib vs. Placebo in the Treatment of Adolescents with Autism Spectrum Disorders (TIDE). Clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT02586935 [Last accessed 5 March 2017].
13. Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H. A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal. 2016; 9:ra110.
14. Palomo V, Perez DI, Perez C, Morales-Garcia JA, Soteras I, Alonso-Gil S, Encinas A, Castro A, Campillo NE, Perez-Castillo A, Gil C, Martinez A. 5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3. J Med Chem. 2012; 55:1645-1661.
15. Palomo V, Soteras I, Perez DI, Perez C, Gil C, Campillo NE, Martinez A. Exploring the binding sites of glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities. J Med Chem. 2011; 54:8461-8470.
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2. Llorens-Marítin M, Jurado J, Hernández F, Ávila J. GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci. 2014; 7:46.
3. Li X, Liu M, Cai Z, Wang G, Li X. Regulation of glycogen synthase kinase-3 during bipolar mania treatment. Bipolar Disord. 2010; 12:741-752.
4. Manoukian AS, Woodgett JR. Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res. 2002; 84:203-229.
5. Piazza F, Manni S, Semenzato G. Novel players in multiple myeloma pathogenesis: role of protein kinases CK2 and GSK3. Leukemia Res. 2013; 37:221-227.
6. Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes. 2000; 49:263-271.
7. Khan I, Tantray MA, Alam MS, Hamid H. Natural and synthetic bioactive inhibitors of glycogen synthase kinase. Eur J Med Chem. 2017; 125:464-477.
8. Eldar-Finkelman H, Licht-Murava A, Pietrokovski S, Eisenstein M. Substrate competitive GSK-3 inhibitors – strategy and implications. Biochim Biophys Acta. 2010; 1804:598-603.
9. Martinez A, Alonso M, Castro A, Pérez C, Moreno FJ. First Non-ATP Competitive Glycogen Synthase Kinase 3 β (GSK-3β) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease. J Med Chem. 2002; 45:1292-1299.
10. Lovestone S, Boada M, Dubois B, Hüll M, Rinne JO, Huppertz HJ, Calero M, Andrés MV, Gómez-Carrillo B, León T, Del Ser T. ARGO investigators. A phase II trial of tideglusib in alzheimer's disease. J Alzheimers Dis. 2015; 45:75-88.
11. Tolosa E, Litvan I, Höglinger GU, Burn D, Lees A, Andrés MV, Gómez-Carrillo B, León T, Del Ser T. TAUROS Investigators. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord. 2014; 29:470-478.
12. Tideglusib vs. Placebo in the Treatment of Adolescents with Autism Spectrum Disorders (TIDE). Clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT02586935 [Last accessed 5 March 2017].
13. Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H. A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal. 2016; 9:ra110.
14. Palomo V, Perez DI, Perez C, Morales-Garcia JA, Soteras I, Alonso-Gil S, Encinas A, Castro A, Campillo NE, Perez-Castillo A, Gil C, Martinez A. 5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3. J Med Chem. 2012; 55:1645-1661.
15. Palomo V, Soteras I, Perez DI, Perez C, Gil C, Campillo NE, Martinez A. Exploring the binding sites of glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities. J Med Chem. 2011; 54:8461-8470.
16. OpenEye Scientific Software. Inc., Santa Fe, NM, USA. 2012.
17. Schrӧdinger LLC. Schrӧdinger Suite 2012. New York, NY. 2012.
18. ADP-GloTM Kinase assay, Protocol KA. ADP-Glo™ Kinase Assay.
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01-05-2017
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“IDENTIFICATION OF NOVEL GLYCOGEN SYNTHASE KINASE-3Β INHIBITOR THROUGH COMBINED SHAPE-BASED SCREENING AND MOLECULAR DOCKING APPROACH”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 9, no. 3, May 2017, pp. 145-8, https://doi.org/10.25004/IJPSDR.2017.090308.
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How to Cite
“IDENTIFICATION OF NOVEL GLYCOGEN SYNTHASE KINASE-3Β INHIBITOR THROUGH COMBINED SHAPE-BASED SCREENING AND MOLECULAR DOCKING APPROACH”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 9, no. 3, May 2017, pp. 145-8, https://doi.org/10.25004/IJPSDR.2017.090308.
