Estudo por Modelagem e Dinâmica Molecular da Interação da Integrina alfa6beta1 com o Domínio Tipo-disintegrina de ADAM2 E ADAM9 Humanas.

• Autor(a) principal: Coronado, Mônika Aparecida
• Data de Publicação: 2008
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações do LNCC
• Texto Completo: https://tede.lncc.br/handle/tede/77
• topic: Dinâmica Molecular; Integrinas; ADAM; Desintegrin-like; SVMP; Molecular Dynamics; Integrins; ADAM; Desintegrin-Like; SVPM; CNPQ::CIENCIAS EXATAS E DA TERRA::CIENCIA DA COMPUTACAO::TEORIA DA COMPUTACAO::COMPUTABILIDADE E MODELOS DE COMPUTACAO

The production of mechanical force on plasma membrane is mediated by integrins, connecting ECM components and cell cytoskeleton. This allows cells to generate traction during migration and tension during ECM remodeling. Integrins are membrane-spaning adhesion receptors that mediate dynamic linkages between intracellular actin cytoskeleton and the extracelullar adhesive matrix, outside-in/inside-out signaling, migration and detachment. Several proteins with diferent functions have already been identified as integrin ligands, and some important candidates as disintegrin-like and cystein-rich domains present in the snake venon metalloproteinases and ADAM (A Disintegrin and Metaloprotease) become important as they interfere in cell signaling pathways mediated by these transmembrane receptors. Thus, the isolation, characterization and structure determination of disintegrin-like domains o_er valuable tools for the development of new therapeutic compounds for a wide range of diseases. These compounds may provide new treatments for diseases such as cancer and inflammation pathologies. However, the mechanisms of ADAM-Integrin interaction have not been well clarified, yet. In this perspective, this study aims to analyze the molecular structure of the alfa6beta1 integrin and the disintegrin-like domain of human ADAM2 and ADAM9. Computational biology methods such as homology modeling and molecular dynamics were used in order to study the dynamics of the interaction of these proteins. Using in silico experimentation, detailed models of human alfa6beta1 and human ADAM 2 and 9 were obtained. Based on these models, the molecular basis of alfa6beta1-ADAMdsld interactions was assessed, and the most important structural components in ligand recognition/discrimination were identified. Using the collected structural information, we designed different small peptide based inhibitors, based on the structure of the interaction loop of human ADAM 9 disintegrin-like domain. Here proposed A9a inhibitor was tested in vitro , showing satisfactory results in blocking cell adhesion on specific substrates by alfa6beta1- laminin affnity inhibition in nanomolar concentrations. Our results also show the effcacy of the constructed models, the power of computational biology tools in new drug-design technologies, and clearly suggest that here presented alfa6beta1 inhibitors are good candidates for further development of new therapeutic agents against inflammation pathologies.