In silico Characterization, ADMET prediction and Molecular Docking studies of few 2/3 carboxylate-4/5/6-monosubstitued indole derivatives as potential GSK-3β inhibitors
Keywords:
GSK-3β, Diabetes mellitus, Indole, docking, ADMETAbstract
Diabetes Mellitus is a leading cause of high mortality rate in the world. Recently, GSK-3β inhibitors showed promising results to treat Diabetes mellitus and several such molecules are in clinical trials. Ethyl 2/3-carboxylate-4/5/6-monosubstituted-1H-indole derivatives were designed with the aim to search new lead molecules. The molecular structures were drawn in ChemBiodraw Ultra© and molecular docking studies were performed by using Schrödinger and AutoDock 1.5.6 software. Few in silico properties such as Log P and toxicity profile were predicted online using SwissADME and PreADMET respectively. Amongst all the designed molecules, few derivatives showed maximum binding affinity in LBD of 6V6L protein. The lipophilic character of the molecules was predicted through their individual Log P Values; molecules with better binding affinities in LBD displayed Log P values of 2.25-3.13. Additionally, some of the designed molecules were subjected to PreADMET for predicting their safety and few were predicted to induce toxic reaction were as others were predicted to be safe in the models that were selected for prediction. Ethyl 2/3-carboxylate-4/5/6-monosubstituted-1H-indole derivative were designed resulting in new molecules with high binding affinities, also few of these molecules were predicted to be non-carcinogenic with low Log P values.
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References
Renfrey S, Featherstone J. Structural proteomics. Nature Reviews. Drug Discovery. 2002 Mar 1; 1 (3):175. DOI: 10.1038/nrd766.
Frame S, Cohen P. GSK-3 takes center stage more than 20 years after its discovery. Biochemical Journal. 2001 Oct 1; 359 (1):1-6. DOI: 10.1042/0264-6021:3590001.
Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. Journal of Cell Science. 2003 Apr 1; 116 (7):1175-86. DOI: 10.1242/jcs.00384.
Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends in Biochemical Sciences. 2004 Feb 1; 29 (2):95-102. DOI: 10.1016/j.tibs.2003.12.004.
Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3β in cellular signaling. Progress in Neurobiology. 2001 Nov 1; 65 (4):391-426. DOI:10.1016/S0301-0082(01)00011-9.
Eldar-Finkelman H. Glycogen synthase kinase 3: an emerging therapeutic target. Trends in Molecular Medicine. 2002 Mar 1; 8 (3):126-32. DOI: 10.1016/s1471-4914(01)02266-3.
Ilouz R, Kaidanovich O. Gurwitz D, et al. Inhibition of glycogen synthase kinase-3β by bivalent zinc ions: insight into the insulin-mimetic action of zinc. Biochemical and Biophysical Research Communications. 2002 Jul 5; 295 (1):102-6. DOI: 10.1016/s0006-291x(02)00636-8.
Meijer L, Thunnissen AM, White AW, et al. Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. Chemistry & Biology. 2000 Jan 1; 7(1):51-63. DOI: 10.1016/s1074-5521(00)00063-6.
Castro A, Martinez A. Inhibition of tau phosphorylation: a new therapeutic strategy for the treatment of Alzheimer’s disease and other neurodegenerative disorders. Expert Opinion on Therapeutic Patents. 2000 Oct 1; 10 (10): 1519-27. DOI:10.1517/13543776.10.10.1519.
Zhang F, Phiel CJ, Spece L, et al. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium: evidence for autoregulation of GSK-3. Journal of Biological Chemistry. 2003 Aug 29; 278 (35): 33067-77. DOI:10.1074/jbc.M212635200.
Leost M, Schultz C, Link A, et al. Paullones are potent inhibitors of glycogen synthase kinase‐3β and cyclin‐dependent kinase 5/p25. European Journal of Biochemistry. 2000 Oct; 267 (19):5983-94. PMID10998059.
Meijer L, Skaltsounis AL, Magiatis P, et al. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chemistry & Biology. 2003 Dec 1; 10 (12):1255-66. DOI: 10.1016/j.chembiol.2003.11.010.
Dessalew N, Bharatam PV. Structure based de novo design of novel glycogen synthase kinase 3 inhibitors. Bioorganic & Medicinal Chemistry. 2007 Jun 1; 15 (11):3728-36. DOI: 10.1016/j.bmc.2007.03.048.
David GS, Marianne B, Ashley EF, et al, Robert WW. 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3. Bioorganic & Medicinal Chemistry Letters. 200; 11: 635-9. DOI: 10.1016/S0960-894X(00)00721-6.
Crisan L, Avram S, Bora A, Kurunczi L, et al., 3D-QSAR study of maleimide analogues as glycogen synthase kinase-3 (gsk-3) inhibitors using comsia approach. Revue Roumaine de Chimie. 2015 Feb 1; 60 (2-3):183-8.
Faulds KJ, Egelston JN, Sedivy LJ, et al. Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells. Journal of Biological Chemistry. 2018 Jul 6; 293 (27):10731-43. DOI: 10.1074/jbc.ra117.001298
Walters WP, Murcko MA. Prediction of ‘drug-likeness’. Advanced Drug Delivery Reviews. 2002 Mar 31; 54 (3):255-71. DOI: 10.1016/S0169-409X(02)00003-0.
Hollingsworth SA, Karplus PA. A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins. BioMolecular Concepts 1(1); 2010, 271–283. DOI:10.1515/bmc.2010.022.
Zhou AQ, O'Hern CS, Regan L. Revisiting the Ramachandran plot from a new angle. Protein Science. 2011 Jul; 20 (7): 1166-71. DOI: 10.1002/pro.644.
Nisha CM, Kumar A, Vimal A, et al. Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor. Journal of Molecular Graphics and Modelling. 2016 Apr 1; 65: 100-7. https://doi.org/10.1016/j.jmgm.2016.03.001.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry. 2010 Jan 30; 31 (2):455-61. DOI: 10.1002/jcc.21334.
Rylander SG, Gotshall B. Optimal population size and the genetic algorithm. Population. 2002; 100 (400):900. Corpus ID: 15152896.
1-(6-((2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)amino)-2-(2,4-dichlorophenyl)pyridin-3-yl)-4-methylpiperazin-2-one
Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 1997 Jan 15; 23 (1-3):3-25. DOI: 10.1016/s0169-409x(00)00129-0.
Veber DF, Johnson SR, Cheng HY, et al., Molecular properties that influence the oral bioavailability of drug candidates. Journal of Medicinal Chemistry. 2002 Jun 6; 45 (12):2615-23. DOI: 10.1021/jm020017n.
Daina A, Michielin O, Zoete V., SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017 Mar 3; 7 (1):1-3. DOI: 10.1038/srep42717.
Doak BC, Over B, Giordanetto F, et al. Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chemistry & Biology. 2014 Sep 18; 21 (9):1115-42. DOI: 10.1016/j.chembiol.2014.08.013.
Moroy G, Martiny VY, Vayer P, et al. Toward in silico structure-based ADMET prediction in drug discovery. Drug Discovery Today. 2012 Jan 1; 17 (1-2):44-55. DOI: 10.1016/j.drudis.2011.10.023.
Martinez A, Castro A, Dorronsoro I et al. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Medicinal Research Reviews. 2002 Jul; 22(4):373-84. DOI: 10.1002/med.10011.
Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends in Pharmacological Sciences. 2004 Sep; 25(9):471-80. DOI: 10.1016/j.tips.2004.07.006.
Lo Monte F, Kramer T, Gu J, et al, Plotkin B, Eldar-Finkelman H, Schmidt B. Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-3α. Journal of Medicinal Chemistry. 2012 May 10; 55 (9):4407-24. DOI: 10.1021/jm300309a
Medina M, Castro A. Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic. Current Opinion in Drug Discovery & Development. 2008 Jul; 11 (4):533-43. DOI: 10.7150/thno.14334
Daina A, Zoete V. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016 Jun 6; 11 (11):1117. DOI: 10.1002/cmdc.201600182
Rinartha, K., Suryasa, W., & Kartika, L. G. S. (2018). Comparative Analysis of String Similarity on Dynamic Query Suggestions. In 2018 Electrical Power, Electronics, Communications, Controls and Informatics Seminar (EECCIS) (pp. 399-404). IEEE.
Suryasa, I. W., Rodríguez-Gámez, M., & Koldoris, T. (2021). Get vaccinated when it is your turn and follow the local guidelines. International Journal of Health Sciences, 5(3), x-xv. https://doi.org/10.53730/ijhs.v5n3.2938
Mahardika, I. M. R., Suyasa, I. G. P. D., Kamaryati, N. P., & Wulandari, S. K. (2021). Health literacy is strongest determinant on self-monitoring blood glucose (SMBG) type 2 DM patients during COVID-19 pandemic at public health centre in Tabanan Regency. International Journal of Health & Medical Sciences, 4(3), 288-297. https://doi.org/10.31295/ijhms.v4n3.1752
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