Proposition of Potential GSK-3ß Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study.

INTRODUCTION: The enzyme Glycogen Synthase Kinase 3-ß (GSK-3ß) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer's Disease (AD). METHODS: In this work, we performed a molecular modeling study of existing GSK-3ß inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability. RESULTS: In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3ß, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability. CONCLUSION: It is concluded that the analogues of GSK-3ß inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment.

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment.

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 ß-secretase and glycogen synthase kinase-3ß. 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.