Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-02-22T23:19:51Z No. of bitstreams: 1 JoseXavierDeLimaNeto_DISSERT.pdf: 20857554 bytes, checksum: 04aea5694e5da65425668c7f81185381 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-02-26T00:31:29Z (GMT) No. of bitstreams: 1 JoseXavierDeLimaNeto_DISSERT.pdf: 20857554 bytes, checksum: 04aea5694e5da65425668c7f81185381 (MD5) / Made available in DSpace on 2016-02-26T00:31:29Z (GMT). No. of bitstreams: 1 JoseXavierDeLimaNeto_DISSERT.pdf: 20857554 bytes, checksum: 04aea5694e5da65425668c7f81185381 (MD5) 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.