MOLECULAR DOCKING STUDIES OF SOME N-AMIDOALKYLATED DERIVATIVES OF 2-AMINO-1,3,4-OXADIAZOLE AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β
Abstract
Alzheimer's disease is a neurodegenerative disease characterized by pathological features of neurofibrillary tangles and β-amyloid plaques in the cerebral cortex. In Alzheimer's disease, tau protein undergoes excess phosphorylation, due to which its threads begin to merge and form neurofibrillary tangles within nerve cells. It has been shown that glycogen synthase kinase-3β is a key factor in the phosphorylation of tau protein, its increased activity leading to pathologies of neurofibrillary tangles and, consequently, to neurodegenerative changes in the brain. In this connection, the search for effective inhibitors of GSK-3β is a very important and urgent task, for their further use in the treatment of Alzheimer's disease.
Aim of research.The aim of this study is to search new inhibitors of GSK-3β among N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole by molecular docking methods.
Materials and methods. We have carried out geometry optimization of analyzed structures within PM3 semi-empirical method, and GSK-3β molecular docking using software ArgusLab 4.0.1. The three-dimensional crystal structure of co-crystallizer GSK-3β and inhibitor has been loaded from the data bank of protein molecules (PDB ID: 3F7Z).
Results. In this study it has been shown that the structures being studied mainly form stronger complexes with the enzyme compared to the known inhibitor. Based on the results of molecular docking, the compounds leaders N-(((5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)amino)methyl)benzamide and 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide have been chosen. The structures of the compounds leaders have been tested for compliance with Lipinski criteria.
Conclusions. Proposed compounds leaders can be recommended for further studies in the treatment of Alzheimer's disease. Despite the good results obtained in silico analysis, it is mandatory to perform biological tests in vitro and in vivo.
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