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Authors
Advisor(s)
Abstract(s)
Os cogumelos apresentam uma grande diversidade na sua composição química, quer de
compostos de alto peso molecular, quer compostos de baixo peso molecular (LMW-“Low Molecular
Weight”). Devido a sua composição química os cogumelos apresentam inúmeras bioactividades,
incluindo: atividade antioxidante, antitumoral, antimicrobiana entre outras. A atividade antitumoral de
cogumelos tem sido associada a presença de polissacarídeos nos cogumelos, no entanto ha uma crescente
base de conhecimento que mostra que compostos LMW também tem um papel essencial na atividade
antitumoral de diferentes espécies de cogumelos. Neste trabalho começou-se por realizar uma pesquisa
bibliográfica, de forma a selecionar compostos LMW, presentes em diferentes espécies de cogumelos e
associados de alguma forma a uma atividade antitumoral. No total selecionaram-se 115 compostos que
formaram a nova biblioteca LMW 2.0, que foi cuidadosamente preparada para estudos in silico.
Em uma segunda parte do trabalho foram realizados estudos de screening virtual da biblioteca
LMW 2.0 utilizando o software de docking molecular AutoDock 4.0, de forma a tentar estimar quais os
compostos da biblioteca que poderão ser os melhores inibidores de 3 proteínas da família Bcl-2: a Bcl-2
(linfoma de célula B 2), a Bcl-XL (linfoma de células B extra grandes) e a MCL-1 (leucemia mieloide-1).
Estas proteínas foram escolhidas pois estão envolvidas nas vias de sinalização da apoptose promovendo a
sua inibição, sendo atualmente conhecidos alvos terapêuticos em processo tumorais. Assim este trabalho
teve como objetivo tentar identificar compostos LMW, presentes em cogumelos, que possam potenciar a
apoptose tumoral, interagindo com a família Bcl-2 de proteínas anti-apoptóticas.
No geral a proteína MCL-1 parece ser mais sensível aos compostos da biblioteca LMW 2.0, com
valores de Ki (constante de inibição) estimados mais baixos, variando entre 17,1 nM e 64,7 nM para os
dez melhores compostos. De seguida os melhores resultados foram obtidos para a Bcl-XL com valores
entre os 51,5 e 185,6 nM e finalmente os resultados menos interessantes foram da Bcl-2 com valores de Ki
entre 140,7 nM e 281 nM. Os compostos glicosilados apresentaram no geral uma melhor capacidade
inibidora estimada. A visualização em detalhe das conformações de interação previstas mostra que a
melhor capacidade inibidora dos compostos glicolisados fica provavelmente a dever-se à interação da
glucose com alguns aminoácidos polares que formam a orla exterior do centro ativo das proteínas em
estudo.
Mushrooms exhibit great diversity in their chemical composition, both in high molecular weight compounds and in low molecular weight (LMW) compounds. Due to their chemical composition mushrooms have numerous bioactivities, including: antioxidant, antitumor, antimicrobial and others. The antitumor activity of mushrooms has been associated with the presence of polysaccharides in mushrooms, however a growing knowledge base as emerged showing that LMW compounds also play an essential role in the antitumor activity of different species of mushrooms. In this work, a bibliographical research was performed in order to select LMW compounds, present in different species of mushrooms, and associated in some way with an antitumor activity. In total, 115 compounds were selected establishing the new LMW 2.0 library. These compounds were carefully prepared for in silico studies and will be made available to the scientific community. In a second part of the work, virtual screening studies of the LMW 2.0 library were performed using AutoDock 4.0 molecular docking software, in an attempt to estimate which library compounds may be the best inhibitors of Bcl-2 family proteins: a Bcl-2 (B-cell lymphoma 2), Bcl-XL (extra-large B-cell lymphoma) and MCL-1 (myeloid leukemia-1). These proteins were chosen because they are involved in the apoptosis signalling pathways opromoting apoptosis inhibition, and are currently known therapeutic targets in several tumor types. Thus, this work aims to identify LMW compounds, present in mushrooms, which could potentially promote tumoral apoptosis by interacting with the Bcl-2 family of anti-apoptotic proteins. Overall the MCL-1 protein appears to be more sensitive to LMW 2.0 library compounds with lower estimated Ki (inhibition constant) values, ranging from 17.1 nM to 64.7 nM for the top ten compounds. The best results were then obtained for Bcl-XL with values between 51.5 and 185.6 nM and finally the less interesting results were Bcl-2 with Ki values between 140.7 nM and 281 nM. Glycosylated compounds generally presented better estimated inhibitory capacity. The detailed visualization of predicted interaction conformations shows that the best inhibitory capacity of the glycosylated compounds is probably due to the interaction of glucose with several polar amino acids that form the outer edge of the active centre of the proteins under study.
Mushrooms exhibit great diversity in their chemical composition, both in high molecular weight compounds and in low molecular weight (LMW) compounds. Due to their chemical composition mushrooms have numerous bioactivities, including: antioxidant, antitumor, antimicrobial and others. The antitumor activity of mushrooms has been associated with the presence of polysaccharides in mushrooms, however a growing knowledge base as emerged showing that LMW compounds also play an essential role in the antitumor activity of different species of mushrooms. In this work, a bibliographical research was performed in order to select LMW compounds, present in different species of mushrooms, and associated in some way with an antitumor activity. In total, 115 compounds were selected establishing the new LMW 2.0 library. These compounds were carefully prepared for in silico studies and will be made available to the scientific community. In a second part of the work, virtual screening studies of the LMW 2.0 library were performed using AutoDock 4.0 molecular docking software, in an attempt to estimate which library compounds may be the best inhibitors of Bcl-2 family proteins: a Bcl-2 (B-cell lymphoma 2), Bcl-XL (extra-large B-cell lymphoma) and MCL-1 (myeloid leukemia-1). These proteins were chosen because they are involved in the apoptosis signalling pathways opromoting apoptosis inhibition, and are currently known therapeutic targets in several tumor types. Thus, this work aims to identify LMW compounds, present in mushrooms, which could potentially promote tumoral apoptosis by interacting with the Bcl-2 family of anti-apoptotic proteins. Overall the MCL-1 protein appears to be more sensitive to LMW 2.0 library compounds with lower estimated Ki (inhibition constant) values, ranging from 17.1 nM to 64.7 nM for the top ten compounds. The best results were then obtained for Bcl-XL with values between 51.5 and 185.6 nM and finally the less interesting results were Bcl-2 with Ki values between 140.7 nM and 281 nM. Glycosylated compounds generally presented better estimated inhibitory capacity. The detailed visualization of predicted interaction conformations shows that the best inhibitory capacity of the glycosylated compounds is probably due to the interaction of glucose with several polar amino acids that form the outer edge of the active centre of the proteins under study.
Description
Mestrado de dupla diplomação com a UTFPR - Universidade Tecnológica Federal do Paraná
Keywords
Screening virtual Docking molecular Família Bcl-2 LMW