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Previous issue date: 2017-12-08 / Quando ativado, o nosso sistema imunol?gico ? capaz de reconhecer e destruir c?lulas tumorais pela ativa??o dos chamados pontos de verifica??o imunol?gicos, essenciais para evitar eventos autoimunes, criando barreiras para a ativa??o de c?lulas T e rejei??o de tumores. Uma das principais vias de inibi??o ? feita pela prote?na PD-1, cuja ativa??o ? explorada por v?rios tipos de tumores cancer?genos, sendo considerado hoje em dia uma abordagem terap?utica nova e importante para o tratamento do c?ncer em geral incluindo o c?ncer de mama.
V?rios anticorpos inibidores dos pontos de verifica??o imunol?gicos j? foram aprovados pela US-FDA (United States - Food and Drug Administration) para interromper a intera??o do receptor PD-1 com os seus ligantes PD-L1 e PDL2, atenuando os sinais inibit?rios e aumentando a resposta antitumoral.Entre eles, a droga pembrolizumab, um anticorpo inibidor do ponto de controle imune, est? sendo amplamente utilizada para bloquear eficientemente um mecanismo protetor do tumor, estimulando as c?lulas T para atacar e destruir as c?lulas cancer?genas.
Dentro deste contexto, o objetivo deste trabalho ? descrever as energias de intera??o entre a prote?na PD-1, o receptor de morte celular programado, e seu inibidor, o f?rmaco pembrolizumab, usando m?todos de bioqu?mica qu?ntica, considerando-se a estrutura cristalina da prote?na PD-1 emcomplexo com seu inibidor. A energia de intera??o entre cada mol?cula de PD-1 e o f?rmaco foi calculada in silico atrav?s de abordagens qu?nticas, levando-se em conta res?duos de amino?cidos atrativos e repulsivos significativos. Foi observado poucas intera??es repulsivas, com forte predomin?ncia da contribui??o atrativa, apontando para uma forte inibi??o do receptor PD-1. Al?m disso, foram analisados v?rios aspectos bioqu?micos, especialmente ?queles relacionados aos pontos de verifica??o imune.
Nossos resultados mostram que o m?todo computacional usado neste trabalho ? um primeiro passo, de baixo custo, para desvendar os res?duos de amino?cidos do f?rmaco que desempenham o papel mais importante na afinidade de liga??o do complexo pembrolizumab / PD-1. Al?m disso, pode ser considerado uma etapa qualitativa para que a imunoterapia se torne uma das ferramentas padr?o, levando ao desenvolvimento de novas e eficientes drogas farmac?uticas contra o c?ncer. / During immunosurveillance, the immune system is capable to recognize and
destroy tumor cells by the activation of the so-called immunological checking
points, essential to avoid autoimmune events, creating barriers to the T-cell
activation and tumor rejection. One of the foremost inhibitory pathways is
done by the PD-1 protein (Programmed cell death protein-1), which is
activated by several types of cancerous tumors, and is now considered a new
and important therapeutic approach for the treatment of cancer in general,
including breast cancer. Several immune checkpoint inhibitor antibodies are already approved by the
US-FDA (United States - Food and Drug Administration) to bind the protein
PD-1, disrupting its interaction with the PD-L1 and PD-L2 ligands, thereby
attenuating inhibitory signals and augmenting the host anti-tumor response.
Among them, the drug pembrolizumab, an immune checkpoint inhibitor
antibody, is being widely used to efficiently blocks a protective mechanism on
cancer cells, triggering the T-cells to destroy them. The aim of this work is to describe the interaction energies between the
protein PD-1 and its drug inhibitor pembrolizumab by using a quantum
biochemistry calculation, taking advantage of the X-ray crystal structure of the
protein PD-1 in complex with its inhibitor. The interaction energy between
each PD-1 molecule and the drug was calculated in silico through quantum
chemistry approaches considering any significant attractive and repulsive
drug?s amino acid residues. Although it was observed few repulsive
interactions, the attractive ones were predominant, pointing out to a strong
inhibition of the programmed cell death receptor. Besides, several
biochemical aspects were analyzed, especially those related to the immune
checking points. Our results show that the computational method used in this work is a low
cost efficient first step to unveil the drug?s amino-acids residues that play the
most important role on the binding affinity of the pembrolizumab/PD-1
complex. Besides, it can be considered a great qualitative step for
immunotherapy to become one of the standard tools leading to the
development of new and effective cancer drugs.
Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/24746 |
Date | 08 December 2017 |
Creators | Tavares, Ana Beatriz Medeiros Lins de Albuquerque |
Contributors | 05011124487, Henriques Neto, Jos? de Miranda, 21367264391, Fulco, Umberto Laino, 67196675487, Albuquerque, Eudenilson Lins de |
Publisher | 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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