IN SILICO STUDIES ON NEW INDAZOLE DERIVATIVES AS GSK-3β INHIBITORS
Keywords:
Physiochemical properties, Nil, Bioactivity score, IndazoleAbstract
Objective: In silico studies were conducted on newly proposed Indazole derivatives as GSK-3β inhibitors to select the best possible drug candidates based on drug properties and bioactivity score of the compounds.
Methods: 31 Indazole derivatives and active GSK-3β Indazole inhibitor 3-(5-chloro-1-methyl-indol-3-yl)-4-[1-[3-(triazol-1-yl)propyl]indazol-3-yl]pyrrole-2,5-dione(IC50 of 0.003 μM) were subjected to predict the mutagenic, tumorigenic, irritant, reproductive risks, and drug-relevant properties using OSIRIS Property Explorer. Further bioactivity scores were determined using Molinspiration online tools.
Results: The results of new GSK-3β inhibitors were compared with potent GSK-3β Indazole inhibitor to examine the prospective of the optimized compounds. The best possible drug candidates were reported after comprehensive analysis on predicted cLogP, solubility, molecular weight, topological molecular polar surface area (TPSA), drug- likeness, drug score properties and bioactivity score for different human targets like GPCR, ion channel, kinase, nuclear receptor, protease and enzymes.
Conclusion: Five compounds 282, 141, 161, 108 and 456 were reported as the best drug like candidates for GSK-3β regulation.
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References
Prashansa A. Drug discovery and development: an insight into Pharmacovigilance. J Pharmacovigilance 2014:2;3.
Phukan S, Babu VS, Kannoji A, Hariharan R, Balaji VN. GSK3β: role in therapeutic landscape and development of modulators. Br J Pharmacol 2010;160(1):1-19.
Akritopoulou-Zanze I, Wakefield BD, Gasiecki A, Kalvin D, Johnson EF, Kovar P, et al. Scaffold oriented synthesis. Part 3: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing [2+3] cycloadditions. Bioorg Med Chem Lett 2011;21(5):1476-9.
Akritopoulou-Zanze I, Wakefield BD, Gasiecki A, Kalvin D, Johnson EF, Kovar P, et al. Scaffold oriented synthesis part 4: Design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions. Bioorg Med Chem Lett 2011;21(5):1480-3.
Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties. J Med Chem 2000;43(20):3714-7.
Molecular Property Explorer, OSIRIS properties [internet]. 2014 [cited 2014 Nov 26]; Available from http: //www.organic-chemistry.org/prog/peo/tox.html.
Padmini E, Inbathamizh L. Quinic acid as a potent drug candidate for prostate cancer–a comparative pharmacokinetic approach. Asian J Pharm Clin Res 2013;6(4):1-7.
Jagadish PC, Soni N, Verma A. Design, synthesis, and in vitro antioxidant activity of 1, 3, 5-trisubstituted-2-pyrazolines derivatives. J Chem 2013;2013:1-7.
Molecular property explorer, OSIRIS properties [internet]. 2014 [cited 2014 Nov 26]; Available from http://www.organic-chemistry.org/prog/peo/drugScore. html.
Molinspiration Cheminformatics. Molinspiration. 2014 [cited 2014 Nov 26]; Available from: http:// www.molinspiration.com/cgi-bin/properties.
Namachivayam B, Raj JS, Kandakatla N. 2D, 3D-QSAR, docking and optimization of 5-substituted-1H-Indazole as inhibitors of GSK3β. Int J Pharm Pharm Sci 2014;6(10):1-8.
Molecular property explorer, OSIRIS properties. 2014 [cited 2014 Nov30]; Available from http://www.organic-chemistry.org/prog/peo/.
Proudfoot JR. Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg Med Chem Lett 2002;12(12):1647-50.
Puratchikody A, Doble M, Ramalakshmi N. Toxicity risk assessment of some novel quinoxalines. Rasayan J Chem 2011;4(3):636-9.
Verma A. Lead finding from phyllanthusdebelis with hepatoprotective potentials. Asi Pac J Trop Biomed 2012;2012:1735-7.
Maryanoff BE, Ye H, Zhang H. Substituted indazolyl (indolyl) maleimide derivatives as kinase inhibitors. WO2005000836 A1; 2005. p. 6.