Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Magn Reson (Gott) ; 2(1): 355-374, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-37904770

RESUMO

Dishevelled (Dvl) proteins are important regulators of the Wnt signalling pathway, interacting through their PDZ domains with the Wnt receptor Frizzled. Blocking the Dvl PDZ-Frizzled interaction represents a potential approach for cancer treatment, which stimulated the identification of small-molecule inhibitors, among them the anti-inflammatory drug Sulindac and Ky-02327. Aiming to develop tighter binding compounds without side effects, we investigated structure-activity relationships of sulfonamides. X-ray crystallography showed high complementarity of anthranilic acid derivatives in the GLGF loop cavity and space for ligand growth towards the PDZ surface. Our best binding compound inhibits Wnt signalling in a dose-dependent manner as demonstrated by TOP-GFP assays (IC50∼50 µM) and Western blotting of ß-catenin levels. Real-time PCR showed reduction in the expression of Wnt-specific genes. Our compound interacted with Dvl-1 PDZ (KD=2.4 µM) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.

2.
ChemMedChem ; 9(7): 1458-62, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24668962

RESUMO

PDZ (PSD-95, Dlg, ZO-1) domains are ubiquitous interaction modules that are involved in many cellular signal transduction pathways. Interference with PDZ-mediated protein-protein interactions has important implications in disease-related signaling processes. For this reason, PDZ domains have gained attention as potential targets for inhibitor design and, in the long run, drug development. Herein we report the development of small molecules to probe the function of the PDZ domain from human AF6 (ALL1-fused gene from chromosome 6), which is an essential component of cell-cell junctions. These compounds bind to AF6 PDZ with substantially higher affinity than the peptide (Ile-Gln-Ser-Val-Glu-Val) derived from its natural ligand, EphB2. In intact cells, the compounds inhibit the AF6-Bcr interaction and interfere with epidermal growth factor (EGF)-dependent signaling.


Assuntos
Cinesinas/antagonistas & inibidores , Miosinas/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Cinesinas/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Miosinas/metabolismo , Domínios PDZ , Peptídeos/química , Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Receptor EphB2/química , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade
3.
ChemMedChem ; 6(8): 1411-22, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21626699

RESUMO

Shank is the central scaffolding protein of the postsynaptic density (PSD) protein complex found in cells of the central nervous system. Cellular studies indicate a prominent role of the protein in the organization of the PSD, in the development of neuronal morphology, in neuronal signaling, and in synaptic plasticity, thus linking Shank functions to the molecular basis of learning and memory. Mutations in the Shank gene have been found in several neuronal disorders including mental retardation, typical autism, and Asperger syndrome. Shank is linked to the PSD complex via its PDZ domain that binds to the C-terminus of guanylate-kinase-associated protein (GKAP). Here, small-molecule inhibitors of Shank3 PDZ domain are developed. A fluorescence polarization assay based on an identified high-affinity peptide is established, and tetrahydroquinoline carboxylates are identified as inhibitors of this protein-protein interaction. Chemical synthesis via a hetero-Diels-Alder strategy is employed for hit optimization, and structure-activity relationship studies are performed. Best hits possess K(i) values in the 10 µM range, and binding to the PDZ domain is confirmed by ¹H,¹5N HSQC NMR experiments. One of the hits crystallizes with the Shank3 PDZ domain. The structure, analyzed at a resolution of 1.85 Å, reveals details of the binding mode. Finally, binding to PDZ domains of PSD-95, syntrophin, and DVL3 was studied using ¹H,¹5N HSQC NMR spectroscopy.


Assuntos
Proteínas de Transporte/química , Quinolinas/química , Sequência de Aminoácidos , Sítios de Ligação , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas do Tecido Nervoso , Domínios PDZ/efeitos dos fármacos , Peptídeos/síntese química , Peptídeos/química , Domínios e Motivos de Interação entre Proteínas , Quinolinas/síntese química , Quinolinas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...