Computational studies of Toll-like receptor 4
This Thesis is focused on the molecular modeling and computational study of the molecular recognition processes involving Pattern Recognition Receptors (PRRs), in particular, Toll-like receptors (TLRs). TLRs are the main actors in innate immunity and are specialized in the recognition of pathogen as...
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/16546 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/16546 |
| Access Level: | acceso abierto |
| Palabra clave: | 615:54(043.2) Pharmaceutical chemistry Química farmacéutica Química farmaceútica 2390 Química Farmacéutica |
| Sumario: | This Thesis is focused on the molecular modeling and computational study of the molecular recognition processes involving Pattern Recognition Receptors (PRRs), in particular, Toll-like receptors (TLRs). TLRs are the main actors in innate immunity and are specialized in the recognition of pathogen associated molecular patterns (PAMPs). In particular, TLR4 is located in the plasma membrane where, together with the MD-2 protein, it binds to lipopolysaccharides, membrane constituents of Gramnegative bacteria, forming a heterodimeric complex. TLR4 agonists can be used as adjuvants in vaccine development and in cancer immunotherapy. TLR4 antagonists have also been studied for their promising application in septic shock, chronic inflammation and autoimmunity. However, the mechanism at atomic level for such activation/inactivation process remains unknown. Our research has been focused on the study of the mechanism of the TLR4/MD-2 system by means of computational approaches. In order to carry out our research objectives, we use a combination of several computational tools: geometry optimization, charges calculations, docking, virtual screening, and molecular dynamics simulations of protein complexes and membranes. The main objective of this Thesis is to elucidate the ligand-protein interactions of TLR4 at atomic detail through computational techniques. Computational methodologies will be applied to the study of the molecular mechanisms involved in the TLRs functionality, and in the recognition of PAMPs. Ligand-protein docking and virtual screening will be used as a source of new compounds able to modulate the TLRs behavior with possible therapeutic applications, and also as biological probes... |
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