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| Author(s): |
Ricardo Pereira Rodrigues
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2014-05-09 |
| Examining board members: |
Carlos Henrique Tomich de Paula da Silva;
Wanda Pereira Almeida;
Ricardo Vessecchi Lourenço;
Carlos Alberto Montanari;
Marco Antonio Alves da Silva
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| Advisor: | Carlos Henrique Tomich de Paula da Silva |
| Abstract | |
Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder characterized by loss of cortical and subcortical neurons. Pathological patterns of Alzheimer\'s disease include the presence of neurofibrillary lesions consisting of the accumulation of amyloid-? protein and the neurofibrillary tangles, resulting of hyperphosphorylated Tau protein. Only two major groups of drugs are used for treatment of AD, cholinesterase inhibitors and antagonists of Nmethyl- D-aspartate receptor. The phosphorylation of proteins by protein kinases constitute one of the major mechanisms which cells use to regulate their metabolism and imbalances in these activities are related to a series of diseases. The high number of isoforms of protein kinase 1 (CK1) found in AD and its association with neurodegenerative markers of indicate their participation in the final stages of degeneration, common to both AD and other neurodegenerative disorders. The approach of CK1 protein as a therapeutic target for AD is promising as the usual compounds used to reduce the production of amyloid-? also block the breakdown of other proteins, causing severe side effects. Increasingly, bioinformatics tools have been used as an aid in reducing costs and time to research. Among these techniques highlights the virtual screening, which includes a set of techniques used sequentially with the aim of select compounds prototypes for the desired target. Ligand and structure-based virtual screening techniches from a 500 thousand database resulted in 35 selected with inhibitory profile for CK1 enzyme were used in this study. The compounds 24, 25, 36, 39 41 and 42 had significan potential for CK1? enzyme inhibition. Among those submitted to enzyme inhibition assays, compound 25 showed selectivity for CK1? , with 40 % inhibition. For those compounds with the best inhibitory concentration at 10 mM and the IC50 will be given an extensive analysis of the results will be held in the future . (AU) | |
| FAPESP's process: | 10/14929-3 - Casein kinase 1 as a target for drug design in Alzheimer's Disease |
| Grantee: | Ricardo Pereira Rodrigues |
| Support Opportunities: | Scholarships in Brazil - Doctorate |