Publicação
Aquaporin inhibitors with anticancer properties - computational screening and functional validation
| Resumo: | Aquaporins (AQPs) are a family of membrane intrinsic proteins that facilitate the diffusion of water, glycerol, and other small solutes across cell membranes. This protein family is composed of 13 members in humans (AQP0-12), which are grouped into three different subgroups according to their permeability profile and sequence homology. Due to their biological importance and widespread distribution, AQPs dysregulation can induce functional changes in different systems/tissues, causing the development of several dis eases, including carcinogenesis. The relationship between AQPs and cancer has been extensively studied, concluding that some AQPs such as AQP5, are overexpressed in a wide variety of tumor cells. Therefore, the discovery of efficient and selective modulators of AQPs has been considered as a promising alternative anticancer treatments. In this project, we proposed to identify and validate functionally promising inhibitors of AQP5 through a multidisciplinary approach that gathered molecular dynamics simulations, molecular docking, Molecular Mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations, and stopped-flow spectroscopy. Using a multi-conformational approach on AQP5 structure, we have enrolled a structure-based virtual screening campaign using the LOPAC and Myria databases from Sigma-Aldrich company, to identify promising modulators of AQP5 permeability. The most promising compounds were then purchased and experimentally tested to evaluate their function modulatory effect on human aquaporin-5. Although we could not identify efficient modulators of the AQP5 function, we were able to gather a high amount of knowledge that will be used in additional studies, always focused on the identification of promising therapeutic anticancer agents targeting AQP5. |
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| Autores principais: | Marques, Jéssica Lopes |
| Assunto: | Aquaporina-5 humana Moduladores de aquaporinas Desenvolvimento de fármacos baseado na estrutura Permeabilidade à água Técnica de fluxo interrompido Teses de mestrado - 2022 |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Aquaporins (AQPs) are a family of membrane intrinsic proteins that facilitate the diffusion of water, glycerol, and other small solutes across cell membranes. This protein family is composed of 13 members in humans (AQP0-12), which are grouped into three different subgroups according to their permeability profile and sequence homology. Due to their biological importance and widespread distribution, AQPs dysregulation can induce functional changes in different systems/tissues, causing the development of several dis eases, including carcinogenesis. The relationship between AQPs and cancer has been extensively studied, concluding that some AQPs such as AQP5, are overexpressed in a wide variety of tumor cells. Therefore, the discovery of efficient and selective modulators of AQPs has been considered as a promising alternative anticancer treatments. In this project, we proposed to identify and validate functionally promising inhibitors of AQP5 through a multidisciplinary approach that gathered molecular dynamics simulations, molecular docking, Molecular Mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations, and stopped-flow spectroscopy. Using a multi-conformational approach on AQP5 structure, we have enrolled a structure-based virtual screening campaign using the LOPAC and Myria databases from Sigma-Aldrich company, to identify promising modulators of AQP5 permeability. The most promising compounds were then purchased and experimentally tested to evaluate their function modulatory effect on human aquaporin-5. Although we could not identify efficient modulators of the AQP5 function, we were able to gather a high amount of knowledge that will be used in additional studies, always focused on the identification of promising therapeutic anticancer agents targeting AQP5. |
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