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Design of a multitarget strategy for proteasome and HDAC inhibition
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Existem duas principais vias de eliminação de proteínas malformadas ou danificadas de forma a promover a longevidade celular: a via proteassomal e a via aggresomal. Já se verificou que inibindo ambas as vias, se obtém níveis sinérgicos de efeitos terapêuticos em pacientes com Mieloma Múltiplo. O imunoproteassoma é uma isoforma do complexo proteico proteassoma com interesse para terapias de cancro, doenças inflamatórias e autoimunes. O objetivo deste trabalho é encontrar compostos com potencial de dupla inibição do imunoproteassoma e HDAC6 humanos através de estudos in silico. Screening Virtual à base de Docking Molecular foi feito para ambos os alvos pretendidos utilizando a base de dados de compostos aprovados para terapia do DrugBank e as interações entre os ligandos e as proteínas foram analisadas para filtrar os resultados dos Screenings Virtuais feitos. Estas análises levaram a quatro compostos de interesse para estudos futuros: Abarelix, Ritonavir, Alprostadil e Paritaprevir.
There are two main pathways through which cells dispose of damaged/misfolded proteins in order to ensure cell viability and health: the proteasome and aggresome pathways. It has been reported that by inhibiting both pathways a synergistic therapeutic effect is achieved in Multiple Myeloma. The immunoproteasome is a proteasome isoform of interest for cancer, inflammatory and autoimmune therapies. The purpose of this work is to find potential dual-inhibitors for the human immunoproteasome and HDAC6 through in silico studies. Docking-based Virtual Screening was done on both intended targets with a database of approved compounds for therapy from DrugBank and ligand-protein interactions were analysed as a way to narrow down the Screening results. This led to four compounds of interest for further study: Abarelix, Ritonavir, Alprostadil and Paritaprevir.
There are two main pathways through which cells dispose of damaged/misfolded proteins in order to ensure cell viability and health: the proteasome and aggresome pathways. It has been reported that by inhibiting both pathways a synergistic therapeutic effect is achieved in Multiple Myeloma. The immunoproteasome is a proteasome isoform of interest for cancer, inflammatory and autoimmune therapies. The purpose of this work is to find potential dual-inhibitors for the human immunoproteasome and HDAC6 through in silico studies. Docking-based Virtual Screening was done on both intended targets with a database of approved compounds for therapy from DrugBank and ligand-protein interactions were analysed as a way to narrow down the Screening results. This led to four compounds of interest for further study: Abarelix, Ritonavir, Alprostadil and Paritaprevir.
Descrição
Tese de mestrado, Química Farmacêutica e Terapêutica, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Proteasome HDAC6 Molecular docking Virtual screening Teses de mestrado - 2020