Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.
:
The GSK-3β enzyme is related to neuronal cell degeneration presented in Alzheimer’s Disease (AD). The objective of this research was to propose analogues of GSK-3β inhibitors through the search for inhibitors of this enzyme, derivation of the pharmacophore patterns of those inhibitors, molecular docking, ADME/Tox prediction, molecular modifi- cations and prediction of synthetic viability. Six analogues were obtained from the inhibitor CID 57399952, since it presents favorable ADME properties and, as disadvantage, only presents mutagenicity. After modifications, all analogues presented absence of alerts of mutagenic and carcinogenic activity, both for rats and mouse, likewise all presented low risks alerts for inhibition of hERG and medium prediction of synthetic viability. It is concluded that the analogues to GSK-3β inhibitors were optimized in relation to the toxicity of template, being presented as promising drug candidates for Alzheimer’s disease treatment.
Objectives:
Carry out an in silico study of chemical substances isolated from the species Drimys angustifolia and Drimys brasiliensis.
Methods:
A theoretical study of global reactivity and QSAR descriptors, MEP construction, molecular docking study was performed to analyze the interaction of substances with acetylcholinesterase of Drosophila melanogaster and prediction of skin permeation and toxicological properties of the substances.
Results:
The chemical reactivity and molecular stability investigation proposed that the substance which presented stability values similar to the standard substance D-limonene was the substance Terpinen-4-ol. The MEPs of the investigated substances were evenly distributed along the hydrogens and oxygens. In molecular docking studies here performed, the substance Myristicin showed interesting and promising results. Regarding to skin permeability, all substances showed low absorbed by the skin, in potential. For toxicological properties, the substance Bicyclogermacrene showed non-carcinogenicity and mutagenicity activity.
Conclusion:
Thus, it was possible to determine that the substance Bicyclogermacrene presented suitable results for future use as a repellent candidate..
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