Como apresentado anteriormente, a diferenciação entre os subtipos de receptor de
serotonina, em especial os receptores 5-HT2B, é um passo importante no desenho de novos
fármacos que visem o sistema monoaminérgico, uma vez que vários compostos acabam sendo eliminados em fases clínicas iniciais de avaliação devido a efeitos colaterais severos relacionados ao mal funcionamento do sistema circulatório.
Desde as primeiras estruturas cristalográficas apresentando a conformação dos receptores de serotonina serem publicadas até hoje, seis novas estruturas tridimensionais foram obtidas, excluindo àquela apresentada no capítulo dois deste trabalho. Nestes cinco
anos, foram publicadas as estruturas de 5-HT1Bcom o agonista ergotamina e o antagonista
metiotepina, 5-HT2B em complexo com LSD e ergotamina e, recentemente o receptor
5-HT2C foi co-cristalografado com ergotamina e ritanserina.
Com essas estruturas em mãos, será possível realizar um estudo comparativo visando caracterizar os pontos chave para a ligação desses compostos em cada subtipo de receptor. Não só isso, mas a presença de ergotamina em todos os três cristais provê uma oportunidade impar para compreender o modo de interação desta molécula com os demais membros dos receptores de serotonina.
Não obstante, muito se tem falado sobre a necessidade de dímeros para o fun-
cionamento de GABAB. Contudo, trabalhos tem mostrado que essa necessidade não é
tão aparente em um nível aminoacídico na região extracelular. Portanto, a publicação da estrutura cristalográfica desse dímero com vários agonistas e antagonistas, além da proteína sem ligantes, nos permite avaliar energetica- e estruturalmente as variações no dímero acarretadas pela interação dos ligantes no bolsão de ligação.
Por fim, a avaliação completa da interação entre os fármacos pembrolizumab e nivolumab, assim como do ligante natural de PD-L1, em complexo com a proteína PD-1 é de grande importância para uma melhor compreensão do funcionamento molecular do receptor. Ademais, outros complexos já estão disponíveis com PD-L1/fármacos e CTLA- 4/fármacos. O que nos abre a porta para o desenvolvimento de uma vasta gama de estudos em imunoterapêuticos.
Destarte, percebe-se que além dos resultados obtidos foram propostos novos tra- balhos que permitirão uma completa descrição do mecanismo funcional dos receptores aqui apresentados. Esta tese constitui um passo a mais para o completo entendimento de sistemas serotonérgico e GABAérgico, bem como de imunoterapias através de anticorpos monoclonais.
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