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Previous issue date: 2015-02-26 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / No sistema nervoso central de mam?feros, a transmiss?o sin?ptica r?pida entre
c?lulas nervosa ? realizada primariamente pelo receptor ?-amino-3-hidroxi-5-metil-4-
isoxazolpropi?nico (AMPA), um Receptor Ionotr?pico de Glutamato, que est? relacionado
com a aprendizagem, mem?ria e homeostase do sistema nervoso. Defici?ncias
em seu funcionamento s?o correlacionadas com o desenvolvimento de muitas desordens
cerebrais, tais como epilepsia, esquizofrenia, autismo, Parkinson e Alzheimer.
O uso dos an?logos de wilardina tem se mostrado uma poderosa ferramenta para o
entendimento dos mecanismos de ativa??o e dessensibiliza??o deste receptor, pois
a modifica??o em um ?nico ?tomo deste ligante permite a observa??o de variados
n?veis de efic?cia. Neste trabalho, tirando vantagem das estruturas de Fl?or Wilardina
(1.35?), Hidrog?nio Wilardina (1.65?), Bromo Wilardina (1.8?) e Iodo Wilardina
(2.15?), co-cristalizadas com o receptor GluA2 com os c?digos 1MQI, 1MQJ, 1MQH e
1MQG, respectivamente, buscou-se diferenciar energeticamente a efic?cia dos quatro
ligantes. Os complexos foram submetidos a c?lculos energ?ticos baseados na teoria
do funcional da densidade (DFT), sob a ?ptica do m?todo do fracionamento molecular
com caps conjugados (MFCC). Os resultados obtidos mostram uma rela??o entre os
valores energ?ticos e a ordem de efic?cia de cada wilardina (FW > HW > BrW > IW),
ainda evidenciam a import?ncia de E705, R485, Y450, S654, T655, T480 e P478 como
os amino?cidos que contribuem mais fortemente com a intera??o dos quatro agonistas
parciais wilardina. Juntamente com isto, delineamos o comportamento de M708,
sendo atra?do pelos ligantes FW e HW, e repelido por BrW e IW. Com os dados relatados
neste trabalho, faz-se poss?vel um melhor entendimento do receptor AMPA, o que
pode servir como auxilio no desenvolvimento de novos f?rmacos para este sistema. / In the central nervous system (CNS) of mammalian, fast synaptic transmission
between nerve cells is performed primarily by ?-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors, an ionotropic glutamate receptor that is related
with learning, memory and homeostasis of the nervous system. Impairments in
their functions are correlated with development of many brain desorders, such as epilepsy,
schizophrenia, autism, Parkinson and Alzheimer. The use of willardiine analogs
has been shown a powerful tool to understanding of activation and desensitization mechanisms
of this receptors, because the modification of a single ligand atom allows
the observation of varying levels of efficacy. In this work, taking advantage of Fluorine
Willardiine (1.35?), Hydrogen Willardiine (1.65?), Bromine Willardiine (1.8?) and Iodine
Willardiine (2.15?) structures co-crystalized with GluA2 with codes 1MQI, 1MQJ,
1MQH and 1MQG, we attempted to energetically differentiate the four ligands efficacy.
The complexes were submitted to energetic calculations based on density functional
theory (DFT), under the optics of molecular fractionation with conjugate caps (MFCC)
method. Obtained results show a relationship between the energetic values and willardiines
efficacy order (FW> HW > BrW > IW), also show the importance of E705, R485,
Y450, S654, T655, T480 e P478 as the amino acids that contribute most strongly with
the interaction of four partial agonists. Furthermore, we outlined the M708 behaviour,
attracted by FW and HW ligands, and repels by BrW and IW. With the datas reported
on this work, it is possible for a better understanding of the AMPA receptor, which can
serve as an aid in the development of new drugs for this system.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/19861 |
| Date | 26 February 2015 |
| Creators | Lima Neto, Jos? Xavier de |
| Contributors | 67196675487, http://lattes.cnpq.br/9579151361576173, Albuquerque, Eudenilson Lins de, 05011124487, http://lattes.cnpq.br/3594651355252245, Corso, Gilberto, 36990485000, http://lattes.cnpq.br/0274040885278760, Mauriz, Paulo Wilson, 01080622870, http://lattes.cnpq.br/7636664451155498, Fulco, Umberto Laino |
| Publisher | Universidade Federal do Rio Grande do Norte, PROGRAMA DE P?S-GRADUA??O EM CI?NCIAS BIOL?GICAS, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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