2D/3D-QSAR, DOCKING AND OPTIMIZATION OF 5-SUBSTITUTED-1H-INDAZOLE AS INHIBITORS OF GSK-3β
Keywords:
Glycogen synthase kinase-3 Beta, Nil, QSAR, Docking, IndazoleAbstract
Objective: Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in several human diseases. GSK-3β is being one of the most attractive therapeutic targets for several decades across the research communities to discover new potent and selective inhibitors of GSK-3β. The objective of the research is to develop new compounds based on the QSAR and molecular docking studies.
Methods: 2D/3D QSAR studies were conducted on a series of 5-substituted Indazole derivatives in order to optimize the GSK-3β inhibitors. Optimized inhibitors were subjected to molecular docking studies to find best inhibitors towards GSK-3β.
Results: The significant QSAR model-3 (2D) and model-6 (3D) elucidate that T_C_N_5, T_2_N_0, SlogP, electrostatic potential (E_451, E_229) and hydrophobicity (H_1052) are important descriptors to conclude the biological activities of compounds. Docking study illustrates Val135, Gln185, Arg141 and Asp200 were essential interacting residues in the active site of the receptor with ligands. Based on QSAR models, 450 compounds were optimized and validated through docking studies.
Conclusion: The best 31 optimized compounds, which showed good interaction energy, docking score and preferred interactions were selected as GSK-3β inhibitors.
Downloads
References
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.
Dasappa JK, Nagendra HG. Preferential selectivity of inhibitors with human tau protein kinase gsk3β elucidates their potential roles for off-target alzheimer's therapy. Int J Alzheimers Dis 2013. p. 1-8.
Doble W, Woodgett J. GSK-3:tricks of the trade for a multitasking kinase. J Cell Sci 2003;116(7):1175-86.
Eom TY, Jope RS. Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3α/β impairs in vivo neural precursor cell proliferation. Biol Psychiatry 2009;66(5):494-502.
Huang HC, Klein PS. Multiple roles for glycogen synthase kinase-3 as a drug target in alzheimers disease. Curr Drug Targets 2006;7(11):1389-97.
Jope RS, Roh MS. Glycogen synthase kinase-3 (gsk3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 2006;7(11):1421-34.
Kim HJ, Choo H, Cho YS, No KT, Pae AN. Novel GSK-3beta inhibitors from sequential virtual screening. Bioorg Med Chem 2008;16(2):636-43.
Martinez A, Castro A, Dorronsoro I, Alonso M. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 2002:22(4):373-84.
Chapter 10: Medina M, Avila J. The Role of Glycogen Synthase Kinase-3 (GSK-3) in Alzheimer’s Disease. Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms, and Therapeutic Targets. Intech Open Access Publisher; 2011. p. 197-222.
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.
Rybakowski JK, Abramowicz M, Szczepankiewicz A, Michalak M, Hauser J, Czekalski. The association of glycogen synthase kinase-3beta (GSK-3β) gene polymorphism with kidney functionin long-term lithium-treated bipolar patients. Int J Bipolar Disord 2013:1(1):1-8.
Thomsen R, Chirstensen MH. A new tequnique for high-accuracy molecular docking. J Med Chem 2006:49(11):3315-21.
Vlife MDS software Package, supplied by Vlife science technologies Pvt. Ltd, Pune, India; 411007.
Wang H, Brown J, Martin M. Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine 2011:53(2):130-40.
Woodgett JR. Molecular cloning and expression of glycogen synthase kinase-3/factorA. EMBO J 1990:9(8):2431-8.