2D/3D-QSAR, DOCKING AND OPTIMIZATION OF 5-SUBSTITUTED-1H-INDAZOLE AS INHIBITORS OF GSK-3β
Journal Title: International Journal of Pharmacy and Pharmaceutical Sciences - Year 2014, Vol 6, Issue 10
Abstract
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.Â
Authors and Affiliations
Namachivayam Balakrishnan, Joseph Santhana Raj, Naresh Kandakatla
Keywords
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